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Inhibitory CD161 receptor recognized as a potential immunotherapy target in glioma-infiltrating T cells by single-cell analysis

Posted in Anticancer Resistance, “Antibody–enzyme conjugates”, Biochemical pathways, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, CRISPR alternative for editing genes without cutting, Etiology, Gene Therapy & Gene Editing Development, Genomic Expression, Glioblastoma, Immunology, Immunotherapy, Innovation in Immunology Diagnostics, Metastasis Process, mRNA Therapeutics, NK Cell-Based Cancer Immunotherapy, tagged , , , , , , , , , , on February 20, 2021| Leave a Comment »

Inhibitory CD161 receptor recognized as a potential immunotherapy target in glioma-infiltrating T cells by single-cell analysis

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

 

Brain tumors, especially the diffused Gliomas are of the most devastating forms of cancer and have so-far been resistant to immunotherapy. It is comprehended that T cells can penetrate the glioma cells, but it still remains unknown why infiltrating cells miscarry to mount a resistant reaction or stop the tumor development.

Gliomas are brain tumors that begin from neuroglial begetter cells. The conventional therapeutic methods including, surgery, chemotherapy, and radiotherapy, have accomplished restricted changes inside glioma patients. Immunotherapy, a compliance in cancer treatment, has introduced a promising strategy with the capacity to penetrate the blood-brain barrier. This has been recognized since the spearheading revelation of lymphatics within the central nervous system. Glioma is not generally carcinogenic. As observed in a number of cases, the tumor cells viably reproduce and assault the adjoining tissues, by and large, gliomas are malignant in nature and tend to metastasize. There are four grades in glioma, and each grade has distinctive cell features and different treatment strategies. Glioblastoma is a grade IV glioma, which is the crucial aggravated form. This infers that all glioblastomas are gliomas, however, not all gliomas are glioblastomas.

Decades of investigations on infiltrating gliomas still take off vital questions with respect to the etiology, cellular lineage, and function of various cell types inside glial malignancies. In spite of the available treatment options such as surgical resection, radiotherapy, and chemotherapy, the average survival rate for high-grade glioma patients remains 1–3 years (1).

A recent in vitro study performed by the researchers of Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard, USA, has recognized that CD161 is identified as a potential new target for immunotherapy of malignant brain tumors. The scientific team depicted their work in the Cell Journal, in a paper entitled, “Inhibitory CD161 receptor recognized in glioma-infiltrating T cells by single-cell analysis.” on 15th February 2021.

To further expand their research and findings, Dr. Kai Wucherpfennig, MD, PhD, Chief of the Center for Cancer Immunotherapy, at Dana-Farber stated that their research is additionally important in a number of other major human cancer types such as 

  • melanoma,
  • lung,
  • colon, and
  • liver cancer.

Dr. Wucherpfennig has praised the other authors of the report Mario Suva, MD, PhD, of Massachusetts Common Clinic; Aviv Regev, PhD, of the Klarman Cell Observatory at Broad Institute of MIT and Harvard, and David Reardon, MD, clinical executive of the Center for Neuro-Oncology at Dana-Farber.

Hence, this new study elaborates the effectiveness of the potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes.

The Study-

IMAGE SOURCE: Experimental Strategy (Mathewson et al., 2021)

 

The group utilized single-cell RNA sequencing (RNA-seq) to mull over gene expression and the clonal picture of tumor-infiltrating T cells. It involved the participation of 31 patients suffering from diffused gliomas and glioblastoma. Their work illustrated that the ligand molecule CLEC2D activates CD161, which is an immune cell surface receptor that restrains the development of cancer combating activity of immune T cells and tumor cells in the brain. The study reveals that the activation of CD161 weakens the T cell response against tumor cells.

Based on the study, the facts suggest that the analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 that codes for CD161 as a candidate inhibitory receptor. This was followed by the use of 

  • CRISPR/Cas9 gene-editing technology to inactivate the KLRB1 gene in T cells and showed that CD161 inhibits the tumor cell-killing function of T cells. Accordingly,
  • genetic inactivation of KLRB1 or
  • antibody-mediated CD161 blockade

enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other forms of human cancers. The work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immune checkpoint targets.

Further, it has been identified that many cancer patients are being treated with immunotherapy drugs that disable their “immune checkpoints” and their molecular brakes are exploited by the cancer cells to suppress the body’s defensive response induced by T cells against tumors. Disabling these checkpoints lead the immune system to attack the cancer cells. One of the most frequently targeted checkpoints is PD-1. However, recent trials of drugs that target PD-1 in glioblastomas have failed to benefit the patients.

In the current study, the researchers found that fewer T cells from gliomas contained PD-1 than CD161. As a result, they said, “CD161 may represent an attractive target, as it is a cell surface molecule expressed by both CD8 and CD4 T cell subsets [the two types of T cells engaged in response against tumor cells] and a larger fraction of T cells express CD161 than the PD-1 protein.”

However, potential side effects of antibody-mediated blockade of the CLEC2D-CD161 pathway remain unknown and will need to be examined in a non-human primate model. The group hopes to use this finding in their future work by

utilizing their outline by expression of KLRB1 gene in tumor-infiltrating T cells in diffuse gliomas to make a remarkable contribution in therapeutics related to immunosuppression in brain tumors along with four other common human cancers ( Viz. melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, and colorectal cancer) and how this may be manipulated for prevalent survival of the patients.

References

(1) Anders I. Persson, QiWen Fan, Joanna J. Phillips, William A. Weiss, 39 – Glioma, Editor(s): Sid Gilman, Neurobiology of Disease, Academic Press, 2007, Pages 433-444, ISBN 9780120885923, https://doi.org/10.1016/B978-012088592-3/50041-4.

Main Source

Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM, Marx S, et al. 2021. Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell.https://www.cell.com/cell/fulltext/S0092-8674(21)00065-9?elqTrackId=c3dd8ff1d51f4aea87edd0153b4f2dc7

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Other related articles published in this Open Access Online Scientific Journal include the following:

 

Single Cell Sequencing:

Part 4.1 in Genomics Volume 2

Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology 

On Amazon.com since 12/28/2019

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4.1.3   Single-cell Genomics: Directions in Computational and Systems Biology – Contributions of Prof. Aviv Regev @Broad Institute of MIT and Harvard, Cochair, the Human Cell Atlas Organizing Committee with Sarah Teichmann of the Wellcome Trust Sanger Institute

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/09/03/single-cell-genomics-directions-in-computational-and-systems-biology-contributions-of-ms-aviv-regev-phd-broad-institute-of-mit-and-harvard-cochair-the-human-cell-atlas-organizing-committee-wit/

 

4.1.4   Cellular Genetics

https://www.sanger.ac.uk/science/programmes/cellular-genetics

 

4.1.5   Cellular Genomics

https://www.garvan.org.au/research/cellular-genomics

 

4.1.6   SINGLE CELL GENOMICS 2019 – sometimes the sum of the parts is greater than the whole, September 24-26, 2019, Djurönäset, Stockholm, Sweden http://www.weizmann.ac.il/conferences/SCG2019/single-cell-genomics-2019

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/05/29/single-cell-genomics-2019-september-24-26-2019-djuronaset-stockholm-sweden/

 

4.1.7   Norwich Single-Cell Symposium 2019, Earlham Institute, single-cell genomics technologies and their application in microbial, plant, animal and human health and disease, October 16-17, 2019, 10AM-5PM

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https://pharmaceuticalintelligence.com/2019/06/04/norwich-single-cell-symposium-2019-earlham-institute-single-cell-genomics-technologies-and-their-application-in-microbial-plant-animal-and-human-health-and-disease-october-16-17-2019-10am-5pm/

 

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https://pharmaceuticalintelligence.com/2019/05/23/newly-found-functions-of-b-cell/

 

4.1.9 RESEARCH HIGHLIGHTS: HUMAN CELL ATLAS

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Chapter 21 in Genomics Volume 1

Genomics Orientations for Personalized Medicine. On Amazon.com since 11/23/2015

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New Treatment in Development for Glioblastoma: Hopes for Sen. John McCain

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Gamma Linolenic Acid (GLA) as a Therapeutic tool in the Management of Glioblastoma

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RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling virus Replication versus Activation of the Adaptive Immune Response

Posted in Antibody Responses Predict Antigen Exposure, Apoptosis, Autophagy-Modulating Proteins, Cell Biology, Signaling & Cell Circuits, Coronavirus Gene Expression, COVID-19, Cytokine Receptor Structure, Genome Biology, Human Antibody Response, Human Circulating Antibody Repertoire, Human Naive B Cell Repertoire, Immunology, Immunotherapy, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, MHC Repertoires for Antigen Prediction, mRNA Therapeutics, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, Serology tests for coronavirus antibodies, Single Cell Genomics, Single-cell sequencing, Synthetic Immunology: Hacking Immune Cells, Vaccinology, Variation in human protein-coding regions, Viral diseases, Virology - Vector-borne DIsease, Virus Infective Acute Respiratory Syndrome: SARS-CoV on May 23, 2020| Leave a Comment »

RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling Virus Replication versus Activation of the Adaptive Immune Response

Curator: Aviva Lev-Ari, PhD, RN – I added colors and bold face

 

UPDATED on 9/8/2020

What bats can teach us about developing immunity to Covid-19 | Free to read

Clive Cookson, Anna Gross and Ian Bott, London

https://www.ft.com/content/743ce7a0-60eb-482d-b1f4-d4de11182fa9?utm_source=Nature+Briefing&utm_campaign=af64422080-briefing-dy-20200908&utm_medium=email&utm_term=0_c9dfd39373-af64422080-43323101

 

UPDATED on 6/29/2020

Another duality and paradox in the Treatment of COVID-19 Patients in ICUs was expressed by Mike Yoffe, MD, PhD, David H. Koch Professor of Biology and Biological Engineering, Massachusetts Institute of Technology. Dr. Yaffe has a joint appointment in Acute Care Surgery, Trauma, and Surgical Critical Care, and in Surgical Oncology @BIDMC

on 6/29 at SOLUTIONS with/in/sight at Koch Institute @MIT

How Are Cancer Researchers Fighting COVID-19? (Part II)” Jun 29, 2020 11:30 AM EST

Mike Yoffe, MD, PhD 

In COVID-19 patients: two life threatening conditions are seen in ICUs:

  • Blood Clotting – Hypercoagulability or Thrombophilia
  • Cytokine Storm – immuno-inflammatory response
  • The coexistence of 1 and 2 – HINDERS the ability to use effectively tPA as an anti-clotting agent while the cytokine storm is present.

Mike Yoffe’s related domain of expertise:

Signaling pathways and networks that control cytokine responses and inflammation

Misregulation of cytokine feedback loops, along with inappropriate activation of the blood clotting cascade causes dysregulation of cell signaling pathways in innate immune cells (neutrophils and macrophages), resulting in tissue damage and multiple organ failure following trauma or sepsis. Our research is focused on understanding the role of the p38-MK2 pathway in cytokine control and innate immune function, and on cross-talk between cytokines, clotting factors, and neutrophil NADPH oxidase-derived ROS in tissue damage, coagulopathy, and inflammation, using biochemistry, cell biology, and mouse knock-out/knock-in models.  We recently discovered a particularly important link between abnormal blood clotting and the complement pathway cytokine C5a which causes excessive production of extracellular ROS and organ damage by neutrophils after traumatic injury.

SOURCE

https://www.bidmc.org/research/research-by-department/surgery/acute-care-surgery-trauma-and-surgical-critical-care/michael-b-yaffe

 

See

The Genome Structure of CORONAVIRUS, SARS-CoV-2

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/05/04/the-genome-structure-of-coronavirus-sars-cov-2-i-awaited-for-this-article-for-60-days/

 

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Open Access Published:May 15, 2020DOI:https://doi.org/10.1016/j.cell.2020.04.026

Highlights

  • SARS-CoV-2 infection induces low IFN-I and -III levels with a moderate ISG response
  • Strong chemokine expression is consistent across in vitro, ex vivo, and in vivo models
  • Low innate antiviral defenses and high pro-inflammatory cues contribute to COVID-19

Summary

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

Graphical Abstract

Figure thumbnail fx1

Keywords

Results

Defining the Transcriptional Response to SARS-CoV-2 Relative to Other Respiratory Viruses

To compare the transcriptional response of SARS-CoV-2 with other respiratory viruses, including MERS-CoV, SARS-CoV-1, human parainfluenza virus 3 (HPIV3), respiratory syncytial virus (RSV), and IAV, we first chose to focus on infection in a variety of respiratory cell lines (Figure 1). To this end, we collected poly(A) RNA from infected cells and performed RNA sequencing (RNA-seq) to estimate viral load. These data show that virus infection levels ranged from 0.1% to more than 50% of total RNA reads (Figure 1A).

Discussion

In the present study, we focus on defining the host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and COVID-19 patients. In general, our data show that the overall transcriptional footprint of SARS-CoV-2 infection was distinct in comparison with other highly pathogenic coronaviruses and common respiratory viruses such as IAV, HPIV3, and RSV. It is noteworthy that, despite a reduced IFN-I and -III response to SARS-CoV-2, we observed a consistent chemokine signature. One exception to this observation is the response to high-MOI infection in A549-ACE2 and Calu-3 cells, where replication was robust and an IFN-I and -III signature could be observed. In both of these examples, cells were infected at a rate to theoretically deliver two functional virions per cell in addition to any defective interfering particles within the virus stock that were not accounted for by plaque assays. Under these conditions, the threshold for PAMP may be achieved prior to the ability of the virus to evade detection through production of a viral antagonist. Alternatively, addition of multiple genomes to a single cell may disrupt the stoichiometry of viral components, which, in turn, may itself generate PAMPs that would not form otherwise. These ideas are supported by the fact that, at a low-MOI infection in A549-ACE2 cells, high levels of replication could also be achieved, but in the absence of IFN-I and -III induction. Taken together, these data suggest that, at low MOIs, the virus is not a strong inducer of the IFN-I and -III system, as opposed to conditions where the MOI is high.
Taken together, the data presented here suggest that the response to SARS-CoV-2 is imbalanced with regard to controlling virus replication versus activation of the adaptive immune response. Given this dynamic, treatments for COVID-19 have less to do with the IFN response and more to do with controlling inflammation. Because our data suggest that numerous chemokines and ILs are elevated in COVID-19 patients, future efforts should focus on U.S. Food and Drug Administration (FDA)-approved drugs that can be rapidly deployed and have immunomodulating properties.

SOURCE

https://www.cell.com/cell/fulltext/S0092-8674(20)30489-X

SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant

Yoriyuki Konno, Izumi Kimura, Keiya Uriu, Masaya Fukushi, Takashi Irie, Yoshio Koyanagi, So Nakagawa, Kei Sato
doi: https://doi.org/10.1101/2020.05.11.088179

Abstract

One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays revealed that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of more than 15,000 SARS-CoV-2 sequences identified a natural variant, in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients, but also describe a possibility of the emergence of natural SARS-CoV-2 quasi-species with extended ORF3b that may exacerbate COVID-19 symptoms.

Highlights

  • ORF3b of SARS-CoV-2 and related bat and pangolin viruses is a potent IFN antagonist

  • SARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV ortholog

  • The anti-IFN activity of ORF3b depends on the length of its C-terminus

  • An ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases

Competing Interest Statement

The authors have declared no competing interest.

Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv

 

SOURCE

https://www.biorxiv.org/content/10.1101/2020.05.11.088179v1

 

 

‘It’s something I have never seen’: How the Covid-19 virus hijacks cells

By SHARON BEGLEY @sxbegle

MAY 21, 2020

RNA (green)
RNA (in green) from the SARS-CoV-2 virus is shown taking over the cells it infects.ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
A deep dive into how the new coronavirus infects cells has found that it orchestrates a hostile takeover of their genes unlike any other known viruses do, producing what one leading scientist calls “unique” and “aberrant” changes.Recent studies show that in seizing control of genes in the human cells it invades, the virus changes how segments of DNA are read, doing so in a way that might explain why the elderly are more likely to die of Covid-19 and why antiviral drugs might not only save sick patients’ lives but also prevent severe disease if taken before infection.“It’s something I have never seen in my 20 years of” studying viruses, said virologist Benjamin tenOever of the Icahn School of Medicine at Mount Sinai, referring to how SARS-CoV-2, the virus that causes Covid-19, hijacks cells’ genomes.The “something” he and his colleagues saw is how SARS-CoV-2 blocks one virus-fighting set of genes but allows another set to launch, a pattern never seen with other viruses. Influenza and the original SARS virus (in the early 2000s), for instance, interfere with both arms of the body’s immune response — what tenOever dubs “call to arms” genes and “call for reinforcement” genes.The first group of genes produces interferons. These proteins, which infected cells release, are biological semaphores, signaling to neighboring cells to activate some 500 of their own genes that will slow down the virus’ ability to make millions of copies of itself if it invades them. This lasts seven to 10 days, tenOever said, controlling virus replication and thereby buying time for the second group of genes to act.This second set of genes produce their own secreted proteins, called chemokines, that emit a biochemical “come here!” alarm. When far-flung antibody-making B cells and virus-killing T cells sense the alarm, they race to its source. If all goes well, the first set of genes holds the virus at bay long enough for the lethal professional killers to arrive and start eradicating viruses.

“Most other viruses interfere with some aspect of both the call to arms and the call for reinforcements,” tenOever said. “If they didn’t, no one would ever get a viral illness”: The one-two punch would pummel any incipient infection into submission.

SARS-CoV-2, however, uniquely blocks one cellular defense but activates the other, he and his colleagues reported in a study published last week in Cell. They studied healthy human lung cells growing in lab dishes, ferrets (which the virus infects easily), and lung cells from Covid-19 patients. In all three, they found that within three days of infection, the virus induces cells’ call-for-reinforcement genes to produce cytokines. But it blocks their call-to-arms genes — the interferons that dampen the virus’ replication.

The result is essentially no brakes on the virus’s replication, but a storm of inflammatory molecules in the lungs, which is what tenOever calls an “unique” and “aberrant” consequence of how SARS-CoV-2 manipulates the genome of its target.

In another new study, scientists in Japan last week identified how SARS-CoV-2 accomplishes that genetic manipulation. Its ORF3b gene produces a protein called a transcription factor that has “strong anti-interferon activity,” Kei Sato of the University of Tokyo and colleagues found — stronger than the original SARS virus or influenza viruses. The protein basically blocks the cell from recognizing that a virus is present, in a way that prevents interferon genes from being expressed.

In fact, the Icahn School team found no interferons in the lung cells of Covid-19 patients. Without interferons, tenOever said, “there is nothing to stop the virus from replicating and festering in the lungs forever.”

That causes lung cells to emit even more “call-for-reinforcement” genes, summoning more and more immune cells. Now the lungs have macrophages and neutrophils and other immune cells “everywhere,” tenOever said, causing such runaway inflammation “that you start having inflammation that induces more inflammation.”

At the same time, unchecked viral replication kills lung cells involved in oxygen exchange. “And suddenly you’re in the hospital in severe respiratory distress,” he said.

In elderly people, as well as those with diabetes, heart disease, and other underlying conditions, the call-to-arms part of the immune system is weaker than in younger, healthier people, even before the coronavirus arrives. That reduces even further the cells’ ability to knock down virus replication with interferons, and imbalances the immune system toward the dangerous inflammatory response.

The discovery that SARS-CoV-2 strongly suppresses infected cells’ production of interferons has raised an intriguing possibility: that taking interferons might prevent severe Covid-19 or even prevent it in the first place, said Vineet Menachery of the University of Texas Medical Branch.

In a study of human cells growing in lab dishes, described in a preprint (not peer-reviewed or published in a journal yet), he and his colleagues also found that SARS-CoV-2 “prevents the vast amount” of interferon genes from turning on. But when cells growing in lab dishes received the interferon IFN-1 before exposure to the coronavirus, “the virus has a difficult time replicating.”

After a few days, the amount of virus in infected but interferon-treated cells was 1,000- to 10,000-fold lower than in infected cells not pre-treated with interferon. (The original SARS virus, in contrast, is insensitive to interferon.)

Ending the pandemic and preventing its return is assumed to require an effective vaccine to prevent infectionand antiviral drugs such as remdesivir to treat the very sick, but the genetic studies suggest a third strategy: preventive drugs.

It’s possible that treatment with so-called type-1 interferon “could stop the virus before it could get established,” Menachery said.

Giving drugs to healthy people is always a dicey proposition, since all drugs have side effects — something considered less acceptable than when a drug is used to treat an illness. “Interferon treatment is rife with complications,” Menachery warned. The various interferons, which are prescribed for hepatitis, cancers, and many other diseases, can cause flu-like symptoms.

But the risk-benefit equation might shift, both for individuals and for society, if interferons or antivirals or other medications are shown to reduce the risk of developing serious Covid-19 or even make any infection nearly asymptomatic.

Interferon “would be warning the cells the virus is coming,” Menachery said, so such pretreatment might “allow treated cells to fend off the virus better and limit its spread.” Determining that will of course require clinical trials, which are underway.

About the Author

Sharon Begley

Senior Writer, Science and Discovery

SOURCE

https://www.statnews.com/2020/05/21/coronavirus-hijacks-cells-in-unique-ways/?utm_source=STAT+Newsletters&utm_campaign=bee97f4883-Daily_Recap&utm_medium=email&utm_term=0_8cab1d7961-bee97f4883-150237109

Other related articles in this Open Access Online Scientific Journal include the following:

 

  • Structure-guided Drug Discovery: (1) The Coronavirus 3CL hydrolase (Mpro) enzyme (main protease) essential for proteolytic maturation of the virus and (2) viral protease, the RNA polymerase, the viral spike protein, a viral RNA as promising two targets for discovery of cleavage inhibitors of the viral spike polyprotein preventing the Coronavirus Virion the spread of infection

Curators and Reporters: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/03/12/structure-guided-drug-discovery-1-the-coronavirus-3cl-hydrolase-mpro-enzyme-main-protease-essential-for-proteolytic-maturation-of-the-virus-and-2-viral-protease-the-rna-polymerase-the-viral/

  • Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – Spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold

Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/03/08/predicting-the-protein-structure-of-coronavirus-inhibition-of-nsp15-can-slow-viral-replication-and-cryo-em-spike-protein-structure-experimentally-verified-vs-ai-predicted-protein-structures-not/

  • Promise of Synthetic Biology for Covid-19 Vaccine

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/03/23/promise-of-synthetic-biology-for-covid-19-vaccine/

  • Glycobiology vs Proteomics: Glycobiologists Prespective in the effort to explain the origin, etiology and potential therapeutics for the Coronavirus Pandemic (COVID-19).

 Curator: Ofer Markman, PhD

https://pharmaceuticalintelligence.com/2020/03/26/glycobiology-vs-proteomics-glycobiologists-prespective-in-the-effort-to-explain-the-origin-etiology-and-potential-therapeutics-for-the-coronavirus-pandemic-covid-19/

  • Worldwide trial uses AI to quickly identify ideal Covid-19 treatments

Reporter : Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/04/09/worldwide-trial-uses-ai-to-quickly-identify-ideal-covid-19-treatments/

  • Updated listing of COVID-19 vaccine and therapeutic trials from NIH Clinical Trials.gov

Curator: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/04/16/updated-listing-of-covid-19-vaccine-and-therapeutic-trials-from-nih-clinical-trials-gov/

  • Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/04/14/actemra-immunosuppressive-which-was-designed-to-treat-rheumatoid-arthritis-but-also-approved-in-2017-to-treat-cytokine-storms-in-cancer-patients-saved-the-sickest-of-all-covid-19-patients/

  • Innate Immune Genes and Two Nasal Epithelial Cell Types: Expression of SARS-CoV-2 Entry Factors – COVID19 Cell Atlas

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/04/23/innate-immune-genes-and-two-nasal-epithelial-cell-types-expression-of-sars-cov-2-entry-factors-covid19-cell-atlas/

Is Remdesivir the miracle cure or a short term cure for COVID-19?

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/05/22/is-remdesivir-the-miracle-cure-or-a-short-term-cure-for-covid-19/

 

  • A Series of Recently Published Papers Report the Development of SARS-CoV2 Neutralizing Antibodies and Passive Immunity toward COVID19

Curator: Stephen J. Williams, Ph.D.

https://pharmaceuticalintelligence.com/2020/05/19/a-series-of-recently-published-papers-report-the-development-of-sars-cov2-neutralizing-antibodies-and-passive-immunity-toward-covid19/

 

  • The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Partnership on May 18, 2020: Leadership of AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Eisai, Eli Lilly, Evotec, Gilead, GlaxoSmithKline, Johnson & Johnson, KSQ Therapeutics, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, and Vir. We also thank multiple NIH institutes (especially NIAID), the FDA, BARDA, CDC, the European Medicines Agency, the Department of Defense, the VA, and the Foundation for NIH

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/05/18/the-accelerating-covid-19-therapeutic-interventions-and-vaccines-activ-partnership-on-may-18-2020/

 

  • Race to develop antibody drugs for COVID-19

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/05/18/race-to-develop-antibody-drugs-for-covid-19/

 

  • The Seasonality of COVID-19

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/05/15/the-seasonality-of-covid-19/

 

  • Powerful AI Tools Being Developed for the COVID-19 Fight

Curator: Stephen J. Williams, Ph.D.

https://pharmaceuticalintelligence.com/2020/05/13/powerful-artificial-intelligence-ai-tools-being-developed-for-the-covid-19-fight/

 

  • Promises on Covid-19 Vaccines

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/05/11/promises-on-covid-19-vaccines/

  • Tweets & Retweets 2020 World Medical Innovation Forum – COVID-19, AI and the Future of Medicine, Featuring Harvard and Industry Leader Insights – MGH & BWH, Virtual Event: Monday, May 11, 8:15 a.m. – 5:15 p.m. ET

Real Time Press Coverage: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/05/11/tweets-retweets-2020-world-medical-innovation-forum-covid-19-ai-and-the-future-of-medicine-featuring-harvard-and-industry-leader-insights-mgh-bwh-virtual-event-mond/

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Pharmaceutical Companies Racing Together to Find a Cure for COVID-19

Posted in Biomarkers & Medical Diagnostics, Diagnostics and Lab Tests, Innovation in Immunology Diagnostics, SARS-CoV-2, Treatment Protocols for COVID-19, Vaccinology, tagged , , , , , , , on April 21, 2020| Leave a Comment »

Pharmaceutical Companies Racing Together to Find a Cure for COVID-19

Reporter: Irina Robu, PhD

The global outbreak has put pressure on companies and the Food and Drug Administration (FDA) to act quickly to make medications available to patients. Several companies are working together to find solutions to treat those infected by the virus and prevent it from spreading.

AstraZeneca is responding to the COVID-19 (novel coronavirus) outbreak to accelerate the development of its di diagnostic testing capabilities to scale-up screening and is also working in partnership with governments on existing screening programs to supplement testing. In addition, AstraZeneca is working to identify monoclonal antibodies to progress towards clinical trial evaluation as a treatment to prevent COVID-19.

Bayer, German multinational pharmaceutical and life sciences company is donating malaria drug, Resochin to the US government for possible use to treat COVID-19. Resochin, made of chloroquine phosphate is a current approve treatment for malaria. China is evaluating it for potential use of COVID-19 and presented decent effects against the first SARS virus in 2003. Doctors consider it a promising treatment for seriously ill coronavirus patients.

AbbVie is research-driven biopharmaceutical company dedicated to developing innovative advanced therapies for four primary therapeutic areas: immunology, oncology, virology and neuroscience. The company declared plans to evaluate HIV medicine as COVID-19 treatment and go into partnerships with health authorities in various countries to explore the efficacy and antiviral activity of the medication.

Boehringer Ingelheim, research driven company  is collaborating with the German Center for Infectious Research to develop therapies and diagnostic tools for COVID-19. Their research teams are screening their entire molecule library with more than one million compounds to identify novel small molecules with activity against the virus.

EMD Serono is the biopharmaceutical business of Merck KGaA, Germany donated interferon beta-1a to French Institute of National Health and Medical Research to use for a clinical trial. Interferon beta-1a is presently in use to treat multiple sclerosis and is under investigation as potential treatment for people with COVID-19 coronavirus disease caused by the SARS-nCoV-2 virus. When confronted with the virus, each cell shoots an emergency flare of interferon to tell the immune system to strengthen its defenses. The interferon beta1a cytokine activates macrophages that engulf antigens and natural killer cells, which are integral to innate immune system. The trial is subsidized by INSERM and its start has been announced by the French Health authorities on March 11. To date, Merck interferon beta-1a is not approved by any regulatory authority for the treatment of COVID-19 or for use as an antiviral agent.

GLAXOSMITHKLINE (GSK) has been working to make vaccine using its established pandemic vaccine adjuvant platform technology available. Sanofi and GSK announced on April 14, 2020 they will collaborate to develop an adjuvanted vaccine for COVID-19, using innovative technology from both companies. Sanofi will donate its S-protein COVID-19 antigen, which is based on recombinant DNA technology. This technology gives an exact genetic match to proteins found on the surface of the virus and the DNA sequence encoding this antigen has been combined into the DNA of the baculovirus expression platform, the basis of Sanofi’s licensed recombinant influenza product in the US.GSK will contribute its proven pandemic adjuvant technology to the collaboration, since it may reduce the amount of vaccine protein required per dose, letting more vaccine doses to be produced and consequently contributing to protect more people.

JOHNSON & JOHNSON has started research into a vaccine, leveraging the same innovative technology used for  Ebola vaccine. Janssen, the pharmaceutical arm of J&J has donated medicines for use in laboratory-based investigations to support efforts in finding a resolution against COVID-19.

Eli Lilly entered into an agreement with AbCellera to co-develop antibody products for the treatment and prevention of COVID-19. The collaboration will leverage AbCellera’s rapid pandemic response platform, established under the DARPA Pandemic Prevention Platform Program, along with Lilly’s global capabilities for rapid development, manufacturing and distribution of therapeutic antibodies. Eli Lilly has also entered an agreement with NIH, NIAID to study baricitinib as an arm in NIAID’s Adaptive COVID-19 treatment trial. Baricitinib, an oral JAK1/JAK2 inhibitor is accepted in more than 65 countries as a treatment for adults with moderately to severely active rheumatoid arthritis. Because of the inflammatory cascade in COVID-19, baricitinib’s anti-inflammatory activity has been hypothesized to have a potential beneficial effect in COVID-19 and needs further study in patients with this infection. Eli Lilly is also using an investigational selective monoclonal antibody against Angiopoientin-2 to Phase 2 testing in pneumonia patients hospitalized with COVID-19 who are at higher risk of delveoping acute respiratory distress syndrome. The company will look whether inhibiting the effects of Angiopoientin-2 with monoclonal antibody which can reduce the progression of acute respiratory distress syndrome. The trial will start in April 2020.

Pfizer and BioNTech work together to develop a potential COVID-19 vaccine which aims to accelerate development of BioNTech’s potential first-in-class COVID-19 mRNA vaccine program, BNT162 . A clinical study is expected to start by the end of April 2020. The collaboration is a continuation of the original agreement in 2019 between the two companies to develop mRNA-based vaccines for prevention of influenza.

Roche, Canada has been designated as a participant in a Phase III clinical trial evaluating the safety and efficacy of one of Roche’s portfolio medicines in hospitalized adult patients with severe COVID-19 pneumonia. The company announced the future launch of its Elecsys Anti-SARS-CoV-2 serology test to detect antibodies in people who have been exposed to SARS-CoV-2 that causes the COVID-19 disease. Antibody testing is vital to help detect people who have been infected by the virus, particularly those who may have been infected but did not display symptoms. Furthermore, the test can support priority screening of high-risk groups who might by now have advanced a certain level of immunity and can continue serving and/or return to work.

Takeda Pharmaceutical Company is initiating the development of an anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG) to treat high-risk individuals with COVID-19, although also investigating whether Takeda’s currently marketed products may be effective treatments for infected patients. Hyperimmune globulins are plasma derived-therapies that have been effective in the treatment of severe acute viral respiratory infections and could be a treatment option for COVID-19. Takeda has the research expertise to develop and manufacture a potential anti-SARS-CoV-2 polyclonal H-IG.

Takeda is presently in discussions  with multiple national health and regulatory agencies and health care partners in the US, Asia, and Europe to expeditiously move the research into anti-SARS-CoV-2 polyclonal H-IG forward. The research requires access to source plasma from people who have efficaciously recovered from COVID-19. The donors have developed antibodies to the virus that could possibly alleviate severity of illness in COVID-19 patients and perhaps prevent it. By transferring the antibodies to a new patient, it may help that person’s immune system respond to the infection and increase their chance of recovery. These efforts to find a vaccine are at an early stage nevertheless being given a high priority within the company.

SOURCE

https://www.marketwatch.com/story/these-nine-companies-are-working-on-coronavirus-treatments-or-vaccines-heres-where-things-stand-2020-03-06

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Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients

Posted in Antibody Responses Predict Antigen Exposure, COVID-19, Cytokine Receptor Structure, Human Antibody Response, Human Circulating Antibody Repertoire, Human Naive B Cell Repertoire, Immunodiagnostics, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Inflammasome, Innovation in Immunology Diagnostics, MHC Repertoires for Antigen Prediction, Population Health Management, Genetics & Pharmaceutical, Protection Against Autoimmune Disease, SARS-CoV-2, Virology - Vector-borne DIsease, Virus Infective Acute Respiratory Syndrome: SARS-CoV, tagged , , on April 14, 2020| Leave a Comment »

Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients

Reporter: Aviva Lev-Ari, PhD, RN

 

Emergency room doctor, near death with coronavirus, saved with experimental treatment

By RICHARD READ SEATTLE BUREAU CHIEF 
APRIL 13, 2020
10:48 PM

Soon after being admitted to his own hospital with a fever, cough and difficulty breathing, he was placed on a ventilator. Five days after that, his lungs and kidneys were failing, his heart was in trouble, and doctors figured he had a day or so to live.

He owes his survival to an elite team of doctors who tried an experimental treatment pioneered in China and used on the sickest of all COVID-19 patients.

Lessons from his dramatic recovery could help doctors worldwide treat other extremely ill COVID-19 patients.

Based on the astronomical level of inflammation in his body and reports written by Chinese and Italian physicians who had treated the sickest COVID-19 patients, the doctors came to believe that it was not the disease itself killing him but his own immune system.

It had gone haywire and began to attack itself — a syndrome known as a “cytokine storm.”

The immune system normally uses proteins called cytokines as weapons in fighting a disease. For unknown reasons in some COVID-19 patients, the immune system first fails to respond quickly enough and then floods the body with cytokines, destroying blood vessels and filling the lungs with fluid.

Dr. Matt Hartman, a cardiologist, said that after four days on the immunosuppressive drug, supplemented by high-dose vitamin C and other therapies, the level of oxygen in Padgett’s blood improved dramatically. On March 23, doctors were able to take him off life support.

Four days later, they removed his breathing tube. He slowly came out of his sedated coma, at first imagining that he was in the top floor of the Space Needle converted to a COVID ward.

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Structure-guided Drug Discovery: (1) The Coronavirus 3CL hydrolase (Mpro) enzyme (main protease) essential for proteolytic maturation of the virus and (2) viral protease, the RNA polymerase, the viral spike protein, a viral RNA as promising two targets for discovery of cleavage inhibitors of the viral spike polyprotein preventing the Coronavirus Virion the spread of infection

Posted in Antibody Responses Predict Antigen Exposure, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, COVID-19, Immunodiagnostics, Immunology, Innovation in Immunology Diagnostics, MHC Repertoires for Antigen Prediction, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Viral diseases, Virology - Vector-borne DIsease, tagged , , , , , , , , , , , , , , , , , , , , , , , on March 12, 2020| Leave a Comment »

Structure-guided Drug Discovery: (1) The Coronavirus 3CL hydrolase (Mpro) enzyme (main protease) essential for proteolytic maturation of the virus and (2) viral protease, the RNA polymerase, the viral spike protein, a viral RNA as promising two targets for discovery of cleavage inhibitors of the viral spike polyprotein preventing the Coronavirus Virion the spread of infection

 

Curators and Reporters: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

 

Therapeutical options to coronavirus (2019-nCoV) include consideration of the following:

(a) Monoclonal and polyclonal antibodies

(b)  Vaccines

(c)  Small molecule treatments (e.g., chloroquinolone and derivatives), including compounds already approved for other indications 

(d)  Immuno-therapies derived from human or other sources

 

 

Structure of the nCoV trimeric spike

The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryo–electron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV. [Bold Face Added by ALA]

Science, this issue p. 1260

Abstract

The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryo–electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.

SOURCE
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
  1. Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.

  2. 2Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  1. ↵†Corresponding author. Email: jmclellan@austin.utexas.edu

  1. ↵* These authors contributed equally to this work.

Science  13 Mar 2020:
Vol. 367, Issue 6483, pp. 1260-1263
DOI: 10.1126/science.abb2507

 

02/04/2020

New Coronavirus Protease Structure Available

PDB data provide a starting point for structure-guided drug discovery

A high-resolution crystal structure of COVID-19 (2019-nCoV) coronavirus 3CL hydrolase (Mpro) has been determined by Zihe Rao and Haitao Yang’s research team at ShanghaiTech University. Rapid public release of this structure of the main protease of the virus (PDB 6lu7) will enable research on this newly-recognized human pathogen.

Recent emergence of the COVID-19 coronavirus has resulted in a WHO-declared public health emergency of international concern. Research efforts around the world are working towards establishing a greater understanding of this particular virus and developing treatments and vaccines to prevent further spread.

RCSB PDB News Imagehttps://doi.org/10.2210/pdb6lu7/pdb

While PDB entry 6lu7 is currently the only public-domain 3D structure from this specific coronavirus, the PDB contains structures of the corresponding enzyme from other coronaviruses. The 2003 outbreak of the closely-related Severe Acute Respiratory Syndrome-related coronavirus (SARS) led to the first 3D structures, and today there are more than 200 PDB structures of SARS proteins. Structural information from these related proteins could be vital in furthering our understanding of coronaviruses and in discovery and development of new treatments and vaccines to contain the current outbreak.

The coronavirus 3CL hydrolase (Mpro) enzyme, also known as the main protease, is essential for proteolytic maturation of the virus. It is thought to be a promising target for discovery of small-molecule drugs that would inhibit cleavage of the viral polyprotein and prevent spread of the infection.

Comparison of the protein sequence of the COVID-19 coronavirus 3CL hydrolase (Mpro) against the PDB archive identified 95 PDB proteins with at least 90% sequence identity. Furthermore, these related protein structures contain approximately 30 distinct small molecule inhibitors, which could guide discovery of new drugs. Of particular significance for drug discovery is the very high amino acid sequence identity (96%) between the COVID-19 coronavirus 3CL hydrolase (Mpro) and the SARS virus main protease (PDB 1q2w). Summary data about these closely-related PDB structures are available (CSV) to help researchers more easily find this information. In addition, the PDB houses 3D structure data for more than 20 unique SARS proteins represented in more than 200 PDB structures, including a second viral protease, the RNA polymerase, the viral spike protein, a viral RNA, and other proteins (CSV).

Public release of the COVID-19 coronavirus 3CL hydrolase (Mpro), at a time when this information can prove most vital and valuable, highlights the importance of open and timely availability of scientific data. The wwPDB strives to ensure that 3D biological structure data remain freely accessible for all, while maintaining as comprehensive and accurate an archive as possible. We hope that this new structure, and those from related viruses, will help researchers and clinicians address the COVID-19 coronavirus global public health emergency.

Update: Released COVID-19-related PDB structures include

  • PDB structure 6lu7 (X. Liu, B. Zhang, Z. Jin, H. Yang, Z. Rao Crystal structure of COVID-19 main protease in complex with an inhibitor N3 doi: 10.2210/pdb6lu7/pdb) Released 2020-02-05
  • PDB structure 6vsb (D. Wrapp, N. Wang, K.S. Corbett, J.A. Goldsmith, C.-L. Hsieh, O. Abiona, B.S. Graham, J.S. McLellan (2020) Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Science doi: 10.1126/science.abb2507) Released 2020-02-26
  • PDB structure 6lxt (Y. Zhu, F. Sun Structure of post fusion core of 2019-nCoV S2 subunit doi: 10.2210/pdb6lxt/pdb) Released 2020-02-26
  • PDB structure 6lvn (Y. Zhu, F. Sun Structure of the 2019-nCoV HR2 Domain doi: 10.2210/pdb6lvn/pdb) Released 2020-02-26
  • PDB structure 6vw1
    J. Shang, G. Ye, K. Shi, Y.S. Wan, H. Aihara, F. Li Structural basis for receptor recognition by the novel coronavirus from Wuhan doi: 10.2210/pdb6vw1/pdb
    Released 2020-03-04
  • PDB structure 6vww
    Y. Kim, R. Jedrzejczak, N. Maltseva, M. Endres, A. Godzik, K. Michalska, A. Joachimiak, Center for Structural Genomics of Infectious Diseases Crystal Structure of NSP15 Endoribonuclease from SARS CoV-2 doi: 10.2210/pdb6vww/pdb
    Released 2020-03-04
  • PDB structure 6y2e
    L. Zhang, X. Sun, R. Hilgenfeld Crystal structure of the free enzyme of the SARS-CoV-2 (2019-nCoV) main protease doi: 10.2210/pdb6y2e/pdb
    Released 2020-03-04
  • PDB structure 6y2f
    L. Zhang, X. Sun, R. Hilgenfeld Crystal structure (monoclinic form) of the complex resulting from the reaction between SARS-CoV-2 (2019-nCoV) main protease and tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (alpha-ketoamide 13b) doi: 10.2210/pdb6y2f/pdb
    Released 2020-03-04
  • PDB structure 6y2g
    L. Zhang, X. Sun, R. Hilgenfeld Crystal structure (orthorhombic form) of the complex resulting from the reaction between SARS-CoV-2 (2019-nCoV) main protease and tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (alpha-ketoamide 13b) doi: 10.2210/pdb6y2g/pdb
    Released 2020-03-04
SOURCE – 02/04/2020

Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease

Originally published 21 Mar 2020 https://doi.org/10.1161/CIRCULATIONAHA.120.046941 Circulation. ;0:null
First page image

Abstract

Coronavirus disease 2019 (COVID-19) is a global pandemic impacting nearly 170 countries/regions and more than 285,000 patients worldwide. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which invades cells through the angiotensin converting enzyme 2 (ACE2) receptor. Among those with COVID-19, there is a higher prevalence of cardiovascular disease and more than 7% of patients suffer myocardial injury from the infection (22% of the critically ill). Despite ACE2 serving as the portal for infection, the role of ACE inhibitors or angiotensin receptor blockers requires further investigation. COVID-19 poses a challenge for heart transplantation, impacting donor selection, immunosuppression, and post-transplant management. Thankfully there are a number of promising therapies under active investigation to both treat and prevent COVID-19. Key Words: COVID-19; myocardial injury; pandemic; heart transplant

SOURCE

https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.046941

ACE2

  • Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW (Apr 2004). “ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis”. The Journal of Biological Chemistry. 279 (17): 17996–8007. doi:10.1074/jbc.M311191200. PMID 14754895.

 

  • Turner AJ, Tipnis SR, Guy JL, Rice G, Hooper NM (Apr 2002). “ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors”. Canadian Journal of Physiology and Pharmacology. 80 (4): 346–53. doi:10.1139/y02-021. PMID 12025971.

 

  •  Zhang, Haibo; Penninger, Josef M.; Li, Yimin; Zhong, Nanshan; Slutsky, Arthur S. (3 March 2020). “Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target”. Intensive Care Medicine. Springer Science and Business Media LLC. doi:10.1007/s00134-020-05985-9. ISSN 0342-4642. PMID 32125455.

 

  • ^ Gurwitz, David (2020). “Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics”. Drug Development Research. doi:10.1002/ddr.21656. PMID 32129518.

 

Angiotensin converting enzyme 2 (ACE2)

is an exopeptidase that catalyses the conversion of angiotensin I to the nonapeptide angiotensin[1-9][5] or the conversion of angiotensin II to angiotensin 1-7.[6][7] ACE2 has direct effects on cardiac functiona and is expressed predominantly in vascular endothelial cells of the heart and the kidneys.[8] ACE2 is not sensitive to the ACE inhibitor drugs used to treat hypertension.[9]

ACE2 receptors have been shown to be the entry point into human cells for some coronaviruses, including the SARS virus.[10] A number of studies have identified that the entry point is the same for SARS-CoV-2,[11] the virus that causes COVID-19.[12][13][14][15]

Some have suggested that a decrease in ACE2 could be protective against Covid-19 disease[16], but others have suggested the opposite, that Angiotensin II receptor blocker drugs could be protective against Covid-19 disease via increasing ACE2, and that these hypotheses need to be tested by datamining of clinical patient records.[17]

REFERENCES

https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_2

 

FOLDING@HOME TAKES UP THE FIGHT AGAINST COVID-19 / 2019-NCOV

by 

We need your help! Folding@home is joining researchers around the world working to better understand the 2019 Coronavirus (2019-nCoV) to accelerate the open science effort to develop new life-saving therapies. By downloading Folding@Home, you can donate your unused computational resources to the Folding@home Consortium, where researchers working to advance our understanding of the structures of potential drug targets for 2019-nCoV that could aid in the design of new therapies. The data you help us generate will be quickly and openly disseminated as part of an open science collaboration of multiple laboratories around the world, giving researchers new tools that may unlock new opportunities for developing lifesaving drugs.

2019-nCoV is a close cousin to SARS coronavirus (SARS-CoV), and acts in a similar way. For both coronaviruses, the first step of infection occurs in the lungs, when a protein on the surface  of the virus binds to a receptor protein on a lung cell. This viral protein is called the spike protein, depicted in red in the image below, and the receptor is known as ACE2. A therapeutic antibody is a type of protein that can block the viral protein from binding to its receptor, therefore preventing the virus from infecting the lung cell. A therapeutic antibody has already been developed for SARS-CoV, but to develop therapeutic antibodies or small molecules for 2019-nCoV, scientists need to better understand the structure of the viral spike protein and how it binds to the human ACE2 receptor required for viral entry into human cells.

Proteins are not stagnant—they wiggle and fold and unfold to take on numerous shapes.  We need to study not only one shape of the viral spike protein, but all the ways the protein wiggles and folds into alternative shapes in order to best understand how it interacts with the ACE2 receptor, so that an antibody can be designed. Low-resolution structures of the SARS-CoV spike protein exist and we know the mutations that differ between SARS-CoV and 2019-nCoV.  Given this information, we are uniquely positioned to help model the structure of the 2019-nCoV spike protein and identify sites that can be targeted by a therapeutic antibody. We can build computational models that accomplish this goal, but it takes a lot of computing power.

This is where you come in! With many computers working towards the same goal, we aim to help develop a therapeutic remedy as quickly as possible. By downloading Folding@home here [LINK] and selecting to contribute to “Any Disease”, you can help provide us with the computational power required to tackle this problem. One protein from 2019-nCoV, a protease encoded by the viral RNA, has already been crystallized. Although the 2019-nCoV spike protein of interest has not yet been resolved bound to ACE2, our objective is to use the homologous structure of the SARS-CoV spike protein to identify therapeutic antibody targets.

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. A novel coronavirus virus was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019.

Image and Caption Credit: Alissa Eckert, MS; Dan Higgins, MAM available at https://phil.cdc.gov/Details.aspx?pid=23311

Structures of the closely related SARS-CoV spike protein bound by therapeutic antibodies may help rapidly design better therapies. The three monomers of the SARS-CoV spike protein are shown in different shades of red; the antibody is depicted in green. [PDB: 6NB7 https://www.rcsb.org/structure/6nb7]

(post authored by Ariana Brenner Clerkin)

References:

PDB 6lu7 structure summary ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI https://www.ebi.ac.uk/pdbe/entry/pdb/6lu7 (accessed Feb 5, 2020).

Tian, X.; Li, C.; Huang, A.; Xia, S.; Lu, S.; Shi, Z.; Lu, L.; Jiang, S.; Yang, Z.; Wu, Y.; et al. Potent Binding of 2019 Novel Coronavirus Spike Protein by a SARS Coronavirus-Specific Human Monoclonal Antibody; preprint; Microbiology, 2020. https://doi.org/10.1101/2020.01.28.923011.

Walls, A. C.; Xiong, X.; Park, Y. J.; Tortorici, M. A.; Snijder, J.; Quispe, J.; Cameroni, E.; Gopal, R.; Dai, M.; Lanzavecchia, A.; et al. Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion. Cell 2019, 176, 1026-1039.e15. https://doi.org/10.2210/pdb6nb7/pdb.

SOURCE

https://foldingathome.org/2020/02/27/foldinghome-takes-up-the-fight-against-covid-19-2019-ncov/

UPDATED 3/13/2020

I am reposting the following Science blog post from Derrick Lowe as is and ask people go browse through the comments on his Science blog In the Pipeline because, as Dr. Lowe states that in this current crisis it is important to disseminate good information as quickly as possible so wanted the readers here to have the ability to read his great posting on this matter of Covid-19.  Also i would like to direct readers to the journal Science opinion letter concerning how important it is to rebuild the trust in good science and the scientific process.  The full link for the following In the Pipeline post is: https://blogs.sciencemag.org/pipeline/archives/2020/03/06/covid-19-small-molecule-therapies-reviewed

A Summary of current potential repurposed therapeutics for COVID-19 Infection from In The Pipeline: A Science blog from Derick Lowe

Covid-19 Small Molecule Therapies Reviewed

By Derek Lowe 

Let’s take inventory on the therapies that are being developed for the coronavirus epidemic. Here is a very thorough list of at Biocentury, and I should note that (like Stat and several other organizations) they’re making all their Covid-19 content free to all readers during this crisis. I’d like to zoom in today on the potential small-molecule therapies, since some of these have the most immediate prospects for use in the real world.

The ones at the front of the line are repurposed drugs that are already approved for human use, for a lot of obvious reasons. The Biocentury list doesn’t cover these, but here’s an article at Nature Biotechnology that goes into detail. Clinical trials are a huge time sink – they sort of have to be, in most cases, if they’re going to be any good – and if you’ve already done all that stuff it’s a huge leg up, even if the drug itself is not exactly a perfect fit for the disease. So what do we have? The compound that is most advanced is probably remdesivir from Gilead, at right. This has been in development for a few years as an RNA virus therapy – it was originally developed for Ebola, and has been tried out against a whole list of single-strand RNA viruses. That includes the related coronaviruses SARS and MERS, so Covid-19 was an obvious fit.

The compound is a prodrug – that phosphoramide gets cleaved off completely, leaving the active 5-OH compound GS-44-1524. It mechanism of action is to get incorporated into viral RNA, since it’s taken up by RNA polymerase and it largely seems to evade proofreading. This causes RNA termination trouble later on, since that alpha-nitrile C-nucleoside is not exactly what the virus is expecting in its genome at that point, and thus viral replication is inhibited.

There are five clinical trials underway (here’s an overview at Biocentury). The NIH has an adaptive-design Phase II trial that has already started in Nebraska, with doses to be changed according to Bayesian readouts along the way. There are two Phase III trials underway at China-Japan Friendship Hospital in Hubei, double-blinded and placebo-controlled (since placebo is, as far as drug therapy goes, the current standard of care). And Gilead themselves are starting two open-label trials, one with no control arm and one with an (unblinded) standard-of-care comparison arm. Those might read out first, depending on when they get off the ground, but will be only rough readouts due to the fast-and-loose trial design. The two Hubei trials and the NIH one will add some rigor to the process, but I’m not sure when they’re going to report. My personal opinion is that I like the chances of this drug more than anything else on this list, but it’s still unlikely to be a game-changer.

There’s an RNA polymerase inhibitor (favipiravir) from Toyama, at right, that’s in a trial in China. It’s a thought – a broad-spectrum agent of this sort would be the sort of thing to try. But unfortunately, from what I can see, it has already turned up as ineffective in in vitro tests. The human trial that’s underway is honestly the sort of thing that would only happen under circumstances like the present: a developing epidemic with a new pathogen and no real standard of care. I hold out little hope for this one, but given that there’s nothing else at present, it probably should be tried. As you’ll see, this is far from the only situation like this.

One of the screens of known drugs in China that also flagged remdesivir noted that the old antimalarial drug chloroquine seemed to be effective in vitro. It had been reported some years back as a possible antiviral, working through more than one mechanism, probably both at viral entry and intracellularly thereafter. That part shouldn’t be surprising – chloroquine’s actual mode(s) of action against malaria parasites are still not completely worked out, either, and some of what people thought they knew about it has turned out to be wrong. There are several trials underway with it at Chinese facilities, some in combination with other agents like remdesivir. Chloroquine has of course been taken for many decades as an antimalarial, but it has a number of liabilities, including seizures, hearing damage, retinopathy and sudden effects on blood glucose. So it’s going to be important to establish just how effective it is and what doses will be needed. Just as with vaccine candidates, it’s possible to do more harm with a rushed treatment than the disease is doing itself

There are several other known antiviral drugs are being tried in China, but I don’t have too much hope for those, either. The neuraminidase inhibitors such as oseltamivir (better known as Tamiflu) were tried against SARS and were ineffective; there is no reason to expect anything versus Covid-19 although these drugs are a component of some drug cocktail trials. The HIV protease therapies such as darunavir and the combination therapy Kaletra are in trials, but that’s also a rather desperate long shot, since there’s no particular reason to think that they will have any such protease inhibition against what this new virus has to offer (and indeed, such agents weren’t much help against SARS in the end, either). The classic interferon/ribavirin combination seems to have had some activity against SARS and MERS, and is in two trials from what I can see. That’s not an awful idea by any means, but it’s not a great one, either: if your viral disease has interferon/ribavirin as a front line therapy, it generally means that there’s nothing really good available. No, unless we get really lucky none of these ideas are going to slow the disease down much.

There are a few other repurposed-protease-inhibitors ideas out there, such as this one. (Edit: I had seen this paper but couldn’t track it down, so thanks to those who sent it along). This paper suggests that the TMPRSS2 protease is important for viral entry on the human-cell-side of the process, a pathway that has been noted for other coronaviruses. And it points out that there is a an approved inhibitor (in Japan) for this enzyme (camostat), so that would definitely seem to be worth a trial, probably in combination with remdesivir.

That’s about it for the existing small molecules, from what I can see. What about new ones? Don’t hold your breath, is all I can say. A drug discovery program from scratch against a new pathogen is, as many readers here well know, not a trivial exercise. As this Bloomberg article details, many such efforts in the past (small molecules and vaccines alike) have come to grief because by the time they had anything to deliver the epidemic itself had passed. Indeed, Gilead’s remdesivir had already been dropped as a potential Ebola therapy.

You will either need to have a target in mind up front or go phenotypic. For the former, what you’d see are better characterizations of the viral protease and more extensive screens against it. Two other big target areas are viral entry (which involves the “spike” proteins on the virus surface and the ACE2 protein on human cells) and viral replication. To the former, it’s worth quickly noting that ACE2 is so much unlike the more familiar ACE protein that none of the cardiovascular ACE inhibitors do anything to it at all. And targeting the latter mechanisms is how remdesivir was developed as a possible Ebola agent, but as you can see, that took time, too. Phenotypic screens are perfectly reasonable against viral pathogens as well, but you’ll need to put time and effort into that assay up front, just as with any phenotypic effort, because as anyone who does that sort of work will tell you, a bad phenotypic screen is a complete waste of everyone’s time.

One of the key steps for either route is identifying an animal model. While animal models of infectious disease can be extremely well translated to human therapy, that doesn’t happen by accident: you need to choose the right animal. Viruses in general (and coronaviruses are no exception) vary widely in their effects in different species, and not just across the gaps of bird/reptile/human and the like. No, you’ll run into things where even the usual set of small mammals are acting differently from each other, with some of them not even getting sick at all. This current virus may well have gone through a couple of other mammalian species before landing on us, but you’ll note that dogs (to pick one) don’t seem to have any problem with it.

All this means that any new-target new-chemical-matter effort against Covid-19 (or any new pathogen) is going to take years, and there is just no way around that. Update: see here for just such an effort to start finding fragment hits for the viral protease. This puts small molecules in a very bimodal distribution: you have the existing drugs that might be repurposed, and are presumably available right now. Nothing else is! At the other end, for completely new therapies you have the usual prospects of drug discovery: years from now, lots of money, low success rate, good luck to all of us. The gap between these two could in theory be filled by vaccines and antibody therapies (if everything goes really, really well) but those are very much their own area and will be dealt with in a separate post.

Either way, the odds are that we (and I mean “we as a species” here) are going to be fighting this epidemic without any particularly amazing pharmacological weapons. Eventually we’ll have some, but I would advise people, pundits, and politicians not to get all excited about the prospects for some new therapies to come riding up over the hill to help us out. The odds of that happening in time to do anything about the current outbreak are very small. We will be going for months, years, with the therapeutic options we have right now. Look around you: what we have today is what we have to work with.

Other related articles published in this Open Access Online Scientific Journal include the following:

 

Group of Researchers @ University of California, Riverside, the University of Chicago, the U.S. Department of Energy’s Argonne National Laboratory, and Northwestern University solve COVID-19 Structure and Map Potential Therapeutics

Reporters: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/03/06/group-of-researchers-solve-covid-19-structure-and-map-potential-therapeutic/

Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – Spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold

Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/03/08/predicting-the-protein-structure-of-coronavirus-inhibition-of-nsp15-can-slow-viral-replication-and-cryo-em-spike-protein-structure-experimentally-verified-vs-ai-predicted-protein-structures-not/

 

Coronavirus facility opens at Rambam Hospital using new Israeli tech

https://www.jpost.com/Israel-News/Coronavirus-facility-opens-at-Rambam-Hospital-using-new-Israeli-tech-619681

 

Read Full Post »

Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold

Posted in BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Engineering, Biological Networks, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, COVID-19, Immunotherapy, Innovation in Immunology Diagnostics, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Proteomics, SARS-CoV-2, Universal Immune Cell Therapies (uICT), Virus Infective Acute Respiratory Syndrome: SARS-CoV, tagged , , on March 8, 2020| Leave a Comment »

Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – Spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold

 

Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. A novel coronavirus virus was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019.

Image and Caption Credit: Alissa Eckert, MS; Dan Higgins, MAM available at https://phil.cdc.gov/Details.aspx?pid=23311

 

UPDATED on 8/9/2020

 

UPDATED on 3/11/2020

Coronaviruses

According to the World Health Organization, coronaviruses make up a large family of viruses named for the crown-like spikes found on their surface (Figure 1). They carry their genetic material in single strands of RNA and cause respiratory problems and fever. Like HIV, coronaviruses can be transmitted between animals and humans.  Coronaviruses have been responsible for the Severe Acute Respiratory Syndrome (SARS) pandemic in the early 2000s and the Middle East Respiratory Syndrome (MERS) outbreak in South Korea in 2015. While the most recent coronavirus, COVID-19, has caused international concern, accessible and inexpensive sequencing is helping us understand COVID-19 and respond to the outbreak quickly.

Figure 1. Coronaviruses with the characteristic spikes as seen under a microscope.

First studies that explore genetic susceptibility to COVID-19 are now being published. The first results indicate that COVID-19 infects cells using the ACE2 cell-surface receptor. Genetic variants in the ACE2 receptor gene are thus likely to influence how effectively COVID-19 can enter the cells in our bodies. Researchers hope to discover genetic variants that confer resistance to a COVID-19 infection, similar to how some variants in the CCR5 receptor gene make people immune to HIV. At Nebula Genomics, we are monitoring the latest COVID-19 research and will add any relevant discoveries to the Nebula Research Library in a timely manner.

The Role of Genomics in Responding to COVID-19

Scientists in China sequenced COVID-19’s genome just a few weeks after the first case was reported in Wuhan. This stands in contrast to SARS, which was discovered in late 2002 but was not sequenced until April of 2003. It is through inexpensive genome-sequencing that many scientists across the globe are learning and sharing information about COVID-19, allowing us to track the evolution of COVID-19 in real-time. Ultimately, sequencing can help remove the fear of the unknown and allow scientists and health professionals to prepare to combat the spread of COVID-19.

Next-generation DNA sequencing technology has enabled us to understand COVID-19 is ~30,000 bases long. Moreover, researchers in China determined that COVID-19 is also almost identical to a coronavirus found in bats and is very similar to SARS. These insights have been critical in aiding in the development of diagnostics and vaccines. For example, the Centers for Disease Control and Prevention developed a diagnostic test to detect COVID-19 RNA from nose or mouth swabs.

Moreover, a number of different government agencies and pharmaceutical companies are in the process of developing COVID-19 vaccines to stop the COVID-19 from infecting more people. To protect humans from infection inactivated virus particles or parts of the virus (e.g. viral proteins) can be injected into humans. The immune system will recognize the inactivated virus as foreign, priming the body to build immunity against possible future infection. Of note, Moderna Inc., the National Institute of Allergy and Infectious Diseases, and Coalition for Epidemic Preparedness Innovations identified a COVID-19 vaccine candidate in a record 42 days. This vaccine will be tested in human clinical trials starting in April.

For more information about COVID-19, please refer to the World Health Organization website.

SOURCE

https://blog.nebula.org/role-of-genomics-coronavirus-covid-19/?utm_source=Nebula%20Genomics&utm_medium=email&utm_campaign=COVID-19

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The problem w/ visionaries is that we don’t recognize them in a timely manner (too late) Ralph Baric @UNCpublichealth and Vineet Menachery deserve recognition for being 5 yrs ahead of #COVID19 nature.com/articles/nm.39 @NatureMedicine pnas.org/content/113/11 @PNASNews via @hoondy

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Senior, A.W., Evans, R., Jumper, J. et al. Improved protein structure prediction using potentials from deep learning. Nature 577, 706–710 (2020). https://doi.org/10.1038/s41586-019-1923-7

Abstract

Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence1. This problem is of fundamental importance as the structure of a protein largely determines its function2; however, protein structures can be difficult to determine experimentally. Considerable progress has recently been made by leveraging genetic information. It is possible to infer which amino acid residues are in contact by analysing covariation in homologous sequences, which aids in the prediction of protein structures3. Here we show that we can train a neural network to make accurate predictions of the distances between pairs of residues, which convey more information about the structure than contact predictions. Using this information, we construct a potential of mean force4 that can accurately describe the shape of a protein. We find that the resulting potential can be optimized by a simple gradient descent algorithm to generate structures without complex sampling procedures. The resulting system, named AlphaFold, achieves high accuracy, even for sequences with fewer homologous sequences. In the recent Critical Assessment of Protein Structure Prediction5 (CASP13)—a blind assessment of the state of the field—AlphaFold created high-accuracy structures (with template modelling (TM) scores6 of 0.7 or higher) for 24 out of 43 free modelling domains, whereas the next best method, which used sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a considerable advance in protein-structure prediction. We expect this increased accuracy to enable insights into the function and malfunction of proteins, especially in cases for which no structures for homologous proteins have been experimentally determined7. https://doi.org/10.1038/s41586-019-1923-7

[ALA added bold face]

COVID-19 outbreak

The scientific community has galvanised in response to the recent COVID-19 outbreak, building on decades of basic research characterising this virus family. Labs at the forefront of the outbreak response shared genomes of the virus in open access databases, which enabled researchers to rapidly develop tests for this novel pathogen. Other labs have shared experimentally-determined and computationally-predicted structures of some of the viral proteins, and still others have shared epidemiological data. We hope to contribute to the scientific effort using the latest version of our AlphaFold system by releasing structure predictions of several under-studied proteins associated with SARS-CoV-2, the virus that causes COVID-19. We emphasise that these structure predictions have not been experimentally verified, but hope they may contribute to the scientific community’s interrogation of how the virus functions, and serve as a hypothesis generation platform for future experimental work in developing therapeutics. We’re indebted to the work of many other labs: this work wouldn’t be possible without the efforts of researchers across the globe who have responded to the COVID-19 outbreak with incredible agility.

Knowing a protein’s structure provides an important resource for understanding how it functions, but experiments to determine the structure can take months or longer, and some prove to be intractable. For this reason, researchers have been developing computational methods to predict protein structure from the amino acid sequence.  In cases where the structure of a similar protein has already been experimentally determined, algorithms based on “template modelling” are able to provide accurate predictions of the protein structure. AlphaFold, our recently published deep learning system, focuses on predicting protein structure accurately when no structures of similar proteins are available, called “free modelling”.  We’ve continued to improve these methods since that publication and want to provide the most useful predictions, so we’re sharing predicted structures for some of the proteins in SARS-CoV-2 generated using our newly-developed methods.

It’s important to note that our structure prediction system is still in development and we can’t be certain of the accuracy of the structures we are providing, although we are confident that the system is more accurate than our earlier CASP13 system. We confirmed that our system provided an accurate prediction for the experimentally determined SARS-CoV-2 spike protein structure shared in the Protein Data Bank, and this gave us confidence that our model predictions on other proteins may be useful. We recently shared our results with several colleagues at the Francis Crick Institute in the UK, including structural biologists and virologists, who encouraged us to release our structures to the general scientific community now. Our models include per-residue confidence scores to help indicate which parts of the structure are more likely to be correct. We have only provided predictions for proteins which lack suitable templates or are otherwise difficult for template modeling.  While these understudied proteins are not the main focus of current therapeutic efforts, they may add to researchers’ understanding of SARS-CoV-2.

Normally we’d wait to publish this work until it had been peer-reviewed for an academic journal. However, given the potential seriousness and time-sensitivity of the situation, we’re releasing the predicted structures as we have them now, under an open license so that anyone can make use of them.

Interested researchers can download the structures here, and can read more technical details about these predictions in a document included with the data. The protein structure predictions we’re releasing are for SARS-CoV-2 membrane protein, protein 3a, Nsp2, Nsp4, Nsp6, and Papain-like proteinase (C terminal domain). To emphasise, these are predicted structures which have not been experimentally verified. Work on the system continues for us, and we hope to share more about it in due course.

Citation:  John Jumper, Kathryn Tunyasuvunakool, Pushmeet Kohli, Demis Hassabis, and the AlphaFold Team, “Computational predictions of protein structures associated with COVID-19”, DeepMind website, 5 March 2020, https://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19

SARS-COV-2 MEMBRANE PROTEIN: A RENDERING OF ONE OF OUR PROTEIN STRUCTURE PREDICTIONS

SOURCES

Computational predictions of protein structures associated with COVID-19

https://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19

15 JAN 2020

AlphaFold: Using AI for scientific discovery 

https://deepmind.com/blog/article/AlphaFold-Using-AI-for-scientific-discovery

 

DeepMind has shared its results with researchers at the Francis Crick Institute, a biomedical research lab in the UK, as well as offering it for download from its website.

“Normally we’d wait to publish this work until it had been peer-reviewed for an academic journal. However, given the potential seriousness and time-sensitivity of the situation, we’re releasing the predicted structures as we have them now, under an open license so that anyone can make use of them,” it said. [ALA added bold face]

There are 93,090 cases of COVID-19, and 3,198 deaths, spread across 76 countries, according to the latest report from the World Health Organization at time of writing. ®

SOURCE

https://www.theregister.co.uk/2020/03/06/deepmind_covid19_outbreak/

 

  • MHC content – The spike protein is thought to be the key to binding to cells via the angiotensin II receptor, the major mechanism the immune system uses to distinguish self from non-self

Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies

Syed Faraz Ahmed 1,† , Ahmed A. Quadeer 1, *,† and Matthew R. McKay 1,2, *

1 Department of Electronic and Computer Engineering, The Hong Kong University of Science and

Technology, Hong Kong, China; sfahmed@connect.ust.hk

2 Department of Chemical and Biological Engineering, The Hong Kong University of Science and

Technology, Hong Kong, China

* Correspondence: eeaaquadeer@ust.hk.com (A.A.Q.); m.mckay@ust.hk (M.R.M.)

† These authors contributed equally to this work.

Received: 9 February 2020; Accepted: 24 February 2020; Published: 25 February 2020

Abstract:

The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2.

Keywords: Coronavirus; 2019-nCoV; 2019 novel coronavirus; SARS-CoV-2; COVID-19; SARS-CoV; MERS-CoV; T cell epitopes; B cell epitopes; vaccine [ALA added bold face]

SOURCE

https://www.mdpi.com/1999-4915/12/3/254/pdf

 

Selected Online COMMENTS to

https://forums.theregister.co.uk/forum/all/2020/03/06/deepmind_covid19_outbreak/

MuscleguySilver badge

Re: Protein structure prediction has been done for ages…

Not quite, Natural Selection does not measure methods, it measures outputs, usually at the organism level.

Sure correct folding is necessary for much protein function and we have prions and chaperone proteins to get it wrong and right.

The only way NS measures methods and mechanisms is if they are very energetically wasteful. But there are some very wasteful ones out there. Beta-Catenin at the end of point of Wnt signalling comes particularly to mind.

Chemist

Re: Does not matter at all

“Determining the structure of the virus proteins might also help in developing a molecule that disrupts the operation of just those proteins, and not anything else in the human body.”

Well it might, but predicting whether a ‘drug’ will NOT interact with any other of the 20000+ protein in complex organisms is well beyond current science. If we could do that we could predict/avoid toxicity and other non-mechanism related side-effects & mostly we can’t.

rob miller

Title

There are 480 structures on PDBe resulting from a search on ‘coronavirus,’ the top hits from MERS and SARS. PR stunt or not, they did win the most recent CASP ‘competition’, so arguably it’s probably our best shot right now – and I am certainly not satisfied that they have been sufficiently open in explaining their algorithms though I have not checked in the last few months. No one is betting anyone’s health on this, and it is not like making one wrong turn in a series of car directions. Latest prediction algorithms incorporate contact map predictions, so it’s not like a wrong dihedral angle sends the chain off in the wrong direction. A decent model would give something to run docking algorithms against with a series of already approved drugs, then we take that shortlist into the lab. A confirmed hit could be an instantly available treatment, no two year wait as currently estimated. [ALA added bold face]

jelabarre59Silver badge

Re: these structure predictions have not been experimentally verified

Naaaah. Can’t possibly be a stupid marketing stunt.

Well yes, a good possibility. But it can also be trying to build on the open-source model of putting it out there for others to build and improve upon. Essentially opening that “peer review” to a larger audience quicker. [ALA added bold face]

We shall see.

Anonymous Coward

Anonymous CowardWhat bothers me, besides the obvious PR stunt, is that they say this prediction is licensed. How can a prediction from software be protected by, I presume, patents? And if this can be protected without even verifying which predictions actually work, what’s to stop someone spitting out millions of random, untested predictions just in case they can claim ownership later when one of them is proven to work? [ALA added bold face]

 

 

SOURCES

 

  • AI-predicted protein structures could unlock vaccine for Wuhan coronavirus… if correct… after clinical trials It’s not quite DeepMind’s ‘Come with me if you want to live’ moment, but it’s close, maybe
By Katyanna Quach 6 Mar 2020 at 05:24 
https://www.theregister.co.uk/2020/03/06/deepmind_covid19_outbreak/

 

Experimentally derived Protein Structures

Experimentally derived by a group of scientists at the University of Texas at Austin and the National Institute of Allergy and Infectious Diseases, an agency under the US National Institute of Health. They both feature a “Spike protein structure.”

  • Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

See all authors and affiliations

Science  19 Feb 2020:
eabb2507
DOI: 10.1126/science.abb2507

 

  • Israeli scientists: We have developed a coronavirus vaccine

https://www.fromthegrapevine.com/health/coronavirus-vaccine-israel-migal-research-institute-david-zigdon

Other related articles published in this Open Access Online Scientific Journal include the following:

 

  • Group of Researchers @ University of California, Riverside, the University of Chicago, the U.S. Department of Energy’s Argonne National Laboratory, and Northwestern University solve COVID-19 Structure and Map Potential Therapeutics

Reporters: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/03/06/group-of-researchers-solve-covid-19-structure-and-map-potential-therapeutic/

 

  • Is It Time for the Virtual Scientific Conference?: Coronavirus, Travel Restrictions, Conferences Cancelled Curator:

Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/03/06/is-it-time-for-the-virtual-scientific-conference-coronavirus-travel-restrictions-conferences-cancelled/

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Impaired antibody development is promoted by chronic viral infection

Posted in Adaptive Immune Response to Biomaterials and Tissue Repair, Allergy and Infectious Diseases, Antibody Responses Predict Antigen Exposure, Autoimmune Inflammatory DIseases, “Antibody–enzyme conjugates”, Biotechnology, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell Processing System in Cell Therapy Process Development, combination immunotherapies., Diagnostic Immunology, Human Antibody Response, Human Circulating Antibody Repertoire, Human Immune System in Health and in Disease, Human Naive B Cell Repertoire, Immune Engineering, Immune Modulatory, Immuno-Oncology & Genomics, Immunodiagnostics, Immunology, Immunotherapy, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Monoclonal antibody therapy, Monoclonal Immunotherapy, Protection Against Autoimmune Disease, Signaling & Cell Circuits, Synergistic Innate and Adaptive Immunotherapy, Synthetic Immunology: Hacking Immune Cells, Universal Immune Cell Therapies (uICT), Viral diseases, tagged , , , , on December 1, 2019| Leave a Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Effective humoral immune responses to infection and immunization are defined by high-affinity antibodies generated as a result of B cell differentiation and selection that occurs within germinal centers (GC). Within the GC, B cells undergo affinity maturation, an iterative and competitive process wherein B cells mutate their immunoglobulin genes (somatic hypermutation) and undergo clonal selection by competing for T cell help. Balancing the decision to remain within the GC and continue participating in affinity maturation or to exit the GC as a plasma cell (PC) or memory B cell (MBC) is critical for achieving optimal antibody avidity, antibody quantity, and establishing immunological memory in response to immunization or infection. Humoral immune responses during chronic infections are often dysregulated and characterized by hypergammaglobulinemia, decreased affinity maturation, and delayed development of neutralizing antibodies. Previous studies have suggested that poor antibody quality is in part due to deletion of B cells prior to establishment of the GC response.

 

In fact the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, researchers used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, the present research defines GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

 

Together, these studies identify a key GC B cell differentiation checkpoint that is dysregulated during chronic infection. Further, it was found that the chronic inflammatory environment, rather than persistent antigen, is sufficient to drive altered GC B cell differentiation during chronic infection even against unrelated antigens. However, the data also indicate that inflammatory circuits are likely linked to perception of antigen stimulation. Nevertheless, this study reveals a B cell-intrinsic program of transcriptional skewing in chronic viral infection that results in shunting out of the cyclic GC B cell process and early GC exit with consequences for antibody quality and hypergammaglobulinemia. These findings have implications for vaccination in individuals with pre-existing chronic infections where antibody responses are often ineffective and suggest that modulation of inflammatory pathways may be therapeutically useful to overcome impaired humoral immunity and foster affinity maturation during chronic viral infections.

 

References:

 

https://www.biorxiv.org/content/10.1101/849844v1

 

https://www.ncbi.nlm.nih.gov/pubmed/25656706

 

https://www.ncbi.nlm.nih.gov/pubmed/27653600

 

https://www.ncbi.nlm.nih.gov/pubmed/26912368

 

https://www.ncbi.nlm.nih.gov/pubmed/26799208

 

https://www.ncbi.nlm.nih.gov/pubmed/23001146

 

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Measles causes amnesia of the immune system

Posted in Allergy and Infectious Diseases, Artificial Intelligence - Breakthroughs in Theories and Technologies, Artificial Intelligence - General, Cell Biology, Cell Biology, Signaling & Cell Circuits, combination immunotherapies., Diagnostic Immunology, Digital HealthCare – biotech & internet joint ventures, Health Care System by Country, HealthCare IT, Healthcare Reform, Human Immune System in Health and in Disease, Immunodiagnostics, Immunology, Immunotherapy, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Monoclonal Immunotherapy, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, tagged , , , , on November 9, 2019| Leave a Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

One of the most contagious diseases known to humankind, measles killed an average of 2.6 million people each year before a vaccine was developed, according to the World Health Organization. Widespread vaccination has slashed the death toll. However, lack of access to vaccination and refusal to get vaccinated means measles still infects more than 7 million people and kills more than 100,000 each year worldwide as reported by WHO. The cases are on the rise, tripling in early 2019 and some experience well-known long-term consequences, including brain damage and vision and hearing loss. Previous epidemiological research into immune amnesia suggests that death rates attributed to measles could be even higher, accounting for as much as 50 percent of all childhood mortality.

 

Over the last decade, evidence has mounted that the measles vaccine protects in two ways. It prevents the well-known acute illness with spots and fever and also appears to protect from other infections over the long term by giving general boost to the immune system. The measles virus can impair the body’s immune memory, causing so-called immune amnesia. By protecting against measles infection, the vaccine prevents the body from losing or “forgetting” its immune memory and preserves its resistance to other infections. Researchers showed that the measles virus wipes out 11% to 73% of the different antibodies that protect against viral and bacterial strains a person was previously immune to like from influenza to herpes virus to bacteria that cause pneumonia and skin infections.

 

This study at Harvard Medical School and their collaborators is the first to measure the immune damage caused by the virus and underscores the value of preventing measles infection through vaccination. The discovery that measles depletes people’s antibody repertoires, partially obliterating immune memory to most previously encountered pathogens, supports the immune amnesia hypothesis. It was found that those who survive measles gradually regain their previous immunity to other viruses and bacteria as they get re-exposed to them. But because this process may take months to years, people remain vulnerable in the meantime to serious complications of those infections and thus booster shots of routine vaccines may be required.

 

VirScan detects antiviral and antibacterial antibodies in the blood that result from current or past encounters with viruses and bacteria, giving an overall snapshot of the immune system. Researchers gathered blood samples from unvaccinated children during a 2013 measles outbreak in the Netherlands and used VirScan to measure antibodies before and two months after infection in 77 children who’d contracted the disease. The researchers also compared the measurements to those of 115 uninfected children and adults. Researchers found a striking drop in antibodies from other pathogens in the measles-infected children that clearly suggested a direct effect on the immune system resembling measles-induced immune amnesia.

 

Further tests revealed that severe measles infection reduced people’s overall immunity more than mild infection. This could be particularly problematic for certain categories of children and adults, the researchers said. The present study observed the effects in previously healthy children only. But, measles is known to hit malnourished children much harder, the degree of immune amnesia and its effects could be even more severe in less healthy populations. Inoculation with the MMR (measles, mumps, rubella) vaccine did not impair children’s overall immunity. The results align with decades of research. Ensuring widespread vaccination against measles would not only help prevent the expected 120,000 deaths that will be directly attributed to measles this year alone, but could also avert potentially hundreds of thousands of additional deaths attributable to the lasting damage to the immune system.

 

References:

 

https://hms.harvard.edu/news/inside-immune-amnesia?utm_source=Silverpop

 

https://science.sciencemag.org/content/366/6465/599

 

www.who.int/immunization/newsroom/measles-data-2019/en/

 

https://www.ncbi.nlm.nih.gov/pubmed/20636817

 

https://www.ncbi.nlm.nih.gov/pubmed/27157064

 

https://www.ncbi.nlm.nih.gov/pubmed/30797735

 

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Newly Found Functions of B Cell

Posted in Adaptive Immune Response to Biomaterials and Tissue Repair, Allergy and Infectious Diseases, Autoimmune Inflammatory DIseases, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, CNS-Immune Interface, combination immunotherapies., Cytokine Receptor Structure, Cytokines, Diagnostic Immunology, Human Immune System in Health and in Disease, Human Naive B Cell Repertoire, Immune Engineering, Immune Modulatory, Immuno-Oncology & Genomics, Immunodiagnostics, Immunology, Immunotherapy, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Integrin-targeted Combination Immunotherapy, Metabolic Immuno-Oncology, Modulating Macrophages in Cancer Immunotherapy, Monoclonal Immunotherapy, NK Cell-Based Cancer Immunotherapy, Protection Against Autoimmune Disease, Synergistic Innate and Adaptive Immunotherapy, Synthetic Immunology: Hacking Immune Cells, Tolerance-inducing Autoimmune Disease Therapeutics, Universal Immune Cell Therapies (uICT), tagged , , , , , , on May 23, 2019| Leave a Comment »

Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

4.1.8

4.1.8   Newly Found Functions of B Cell, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 4: Single Cell Genomics

The importance of B cells to human health is more than what is already known. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts. B cells have been a subject of fascination since at least the 1800s. The notion of a humoral branch to immunity emerged from the work of and contemporaries studying B cells in the early 1900s.

Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory. This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells. Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants).

With so much already known, B cell biology might be considered ‘‘done’’ with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done.

Multiple self-tolerance checkpoints exist to remove autoreactive specificities from the B cell repertoire or to limit the ability of such cells to secrete autoantigen-binding antibody. These include receptor editing and deletion in immature B cells, competitive elimination of chronically autoantigen binding B cells in the periphery, and a state of anergy that disfavors PC (plasma cell) differentiation. Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring.

Autoantibodies are pathogenic in a number of human diseases including SLE (Systemic lupus erythematosus), pemphigus vulgaris, Grave’s disease, and myasthenia gravis. B cell depletion therapy using anti-CD20 antibody has been protective in some of these diseases such as pemphigus vulgaris, but not others such as SLE and this appears to reflect the contribution of SLPC (Short lived plasma cells) versus LLPC (Long lived plasma cells) to autoantibody production and the inability of even prolonged anti-CD20 treatment to eliminate the later. These clinical findings have added to the importance of understanding what factors drive SLPC versus LLPC development and what the requirements are to support LLPCs.

B cell depletion therapy has also been efficacious in several other autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis (RA). While the potential contributions of autoantibodies to the pathology of these diseases are still being explored, autoantigen presentation has been posited as another mechanism for B cell disease-promoting activity.

In addition to autoimmunity, B cells play an important role in allergic diseases. IgE antibodies specific for allergen components sensitize mast cells and basophils for rapid degranulation in response to allergen exposures at various sites, such as in the intestine (food allergy), nose (allergic rhinitis), and lung (allergic asthma). IgE production may thus be favored under conditions that induce weak B cell responses and minimal GC (Germinal center) activity, thereby enabling IgE+ B cells and/or PCs to avoid being outcompeted by IgG+ cells. Aside from IgE antibodies, B cells may also contribute to allergic inflammation through their interactions with T cells.

B cells have also emerged as an important source of the immunosuppressive cytokine IL-10. Mouse studies revealed that B cell-derived IL-10 can promote recovery from EAE (Experimental autoimmune encephalomyelitis) and can be protective in models of RA and type 1 diabetes. Moreover, IL-10 production from B cells restrains T cell responses during some viral and bacterial infections. These findings indicate that the influence of B cells on the cytokine milieu will be context dependent.

The presence of B cells in a variety of solid tumor types, including breast cancer, ovarian cancer, and melanoma, has been associated in some studies with a positive prognosis. The mechanism involved is unclear but could include antigen presentation to CD4 and CD8 T cells, antibody production and subsequent enhancement of presentation, or by promoting tertiary lymphoid tissue formation and local T cell accumulation. It is also noteworthy that B cells frequently make antibody responses to cancer antigens and this has led to efforts to use antibodies from cancer patients as biomarkers of disease and to identify immunotherapy targets.

Malignancies of B cells themselves are a common form of hematopoietic cancer. This predilection arises because the gene modifications that B cells undergo during development and in immune responses are not perfect in their fidelity, and antibody responses require extensive B cell proliferation. The study of B cell lymphomas and their associated genetic derangements continues to be illuminating about requirements for normal B cell differentiation and signaling while also leading to the development of targeted therapies.

Overall this study attempted to capture some of the advances in the understanding of B cell biology that have occurred since the turn of the century. These include important steps forward in understanding how B cells encounter antigens, the co-stimulatory and cytokine requirements for their proliferation and differentiation, and how properties of the B cell receptor, the antigen, and helper T cells influence B cell responses. Many advances continue to transform the field including the impact of deep sequencing technologies on understanding B cell repertoires, the IgA-inducing microbiome, and the genetic defects in humans that compromise or exaggerate B cell responses or give rise to B cell malignancies.

Other advances that are providing insight include:

  • single-cell approaches to define B cell heterogeneity,
  • glycomic approaches to study effector sugars on antibodies,
  • new methods to study human B cell responses including CRISPR-based manipulation, and
  • the use of systems biology to study changes at the whole organism level.

With the recognition that B cells and antibodies are involved in most types of immune response and the realization that inflammatory processes contribute to a wider range of diseases than previously believed, including, for example, metabolic syndrome and neurodegeneration, it is expected that further

  • basic research-driven discovery about B cell biology will lead to more and improved approaches to maintain health and fight disease in the future.

References:

https://www.cell.com/cell/fulltext/S0092-8674(19)30278-8

https://onlinelibrary.wiley.com/doi/full/10.1002/hon.2405

https://www.pnas.org/content/115/18/4743

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12911

https://cshperspectives.cshlp.org/content/10/5/a028795

https://www.sciencedirect.com/science/article/abs/pii/S0049017218304955

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Immunoediting can be a constant defense in the cancer landscape

Posted in Anticancer Resistance, Apoptosis, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Surgery of the Heart, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell death pathways, Cell Processing System in Cell Therapy Process Development, cell-based therapy, Childhood cancer, Circulating Tumor Cells (CTC), combination immunotherapies., Efficacy of Anti-Tumor T Cells, Engineering Better T Cells, Engineering Enhanced Cancer Vaccines, Funding Opportunities for Cancer Research, Human Immune System in Health and in Disease, Imaging-based Cancer Patient Management, Immune Modulatory, Immuno-Oncology & Genomics, Immunology, Immunotherapy, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Integrin-targeted Combination Immunotherapy, Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood, Liquid Biopsy: Circulating Tumor Cells in Urine and Blood, Metabolic Immuno-Oncology, Microbiome and Responses to Cancer Therapy, MicroEngineering Cell-Tissue & Systems, Modulating Macrophages in Cancer Immunotherapy, Monoclonal Immunotherapy, NK Cell-Based Cancer Immunotherapy, Pancreatic cancer, Pharmacotherapy and Cell Activity, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Precision Cancer Medicine, Prostate Cancer: Monitoring vs Treatment, RNA Biology, Cancer and Therapeutics, Signaling & Cell Circuits, Single Cell Genomics, stem cell biology and patient-specific, Stem Cells for Regenerative Medicine, Synergistic Innate and Adaptive Immunotherapy, Synthetic Immunology: Hacking Immune Cells, Universal Immune Cell Therapies (uICT), Voices of Patients and Healthcare Providers, tagged , , , , on March 16, 2019| Leave a Comment »

Immuno-editing can be a constant defense in the cancer landscape, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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