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Sex Differences in Immune Responses that underlie COVID-19 Disease Outcomes

Reporter: Aviva Lev-Ari, PhD, RN – color and bold face added

 

This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Sex differences in immune responses that underlie COVID-19 disease outcomes

Abstract

A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)1–5. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in

  • viral loads,
  • SARS-CoV-2-specific antibody titers,
  • plasma cytokines, as well as
  • blood cell phenotyping in COVID-19 patients.

By focusing our analysis on patients with moderate disease who had not received immunomodulatory medications, our results revealed that

  • male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. In contrast,
  • female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age.
  • Importantly, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients.
  • Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients.
  • These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide an important basis for the development of
  • a sex-based approach to the treatment and care of men and women with COVID-19.

Author information

Affiliations

Consortia

Corresponding author

Correspondence to Akiko Iwasaki.

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Apr 22, 2020

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Dmitry Korkin is a professor of bioinformatics and computational biology at Worcester Polytechnic Institute, where he specializes in bioinformatics of complex disease, computational genomics, systems biology, and biomedical data analytics. I came across Dmitry’s work when in February his group used the viral genome of the COVID-19 to reconstruct the 3D structure of its major viral proteins and their interactions with human proteins, in effect creating a structural genomics map of the coronavirus and making this data open and available to researchers everywhere. We talked about the biology of COVID-19, SARS, and viruses in general, and how computational methods can help us understand their structure and function in order to develop antiviral drugs and vaccines.
This conversation is part of the Artificial Intelligence podcast.
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OUTLINE: 0:00 – Introduction 2:33 – Viruses are terrifying and fascinating 6:02 – How hard is it to engineer a virus? 10:48 – What makes a virus contagious? 29:52 – Figuring out the function of a protein 53:27 – Functional regions of viral proteins 1:19:09 – Biology of a coronavirus treatment 1:34:46 – Is a virus alive? 1:37:05 – Epidemiological modeling 1:55:27 – Russia 2:02:31 – Science bobbleheads 2:06:31 – Meaning of life
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Contagious

We are in the midst of a pandemic that is impacting people and society in ways that are hard to grasp. The most apparent impact is on physical health. It also effects our attitudes in society, our economy and our cultural life. Throughout history, humanity has had to face the challenge of understanding, managing and fighting viruses.

In the exhibition Contagious we are highlighting Nobel Prize-awarded researchers who have expanded our knowledge about viruses, mapped our immune system and developed vaccines. We also examine the perspectives from Literature and Economics Laureates about the impact of epidemics on life and society. Visit us at the museum or on these pages.

Museums have an important role to play in times of crisis, since they can help people tackle existential questions and provide a broader context. The Nobel Museum is about ideas that have changed the world. The Nobel Prize points to the ability of humans to find solutions to difficult challenges that we face time and time again. It is a source of hope, even in the midst of the crisis.

SOURCE

Nobel Prize Museum

https://nobelprizemuseum.se/en/whats-on/contagious/?utm_content=contagious_text

Coronavirus

On March 11 this year, the World Health Organization announced that the spread of the coronavirus should be classified as a pandemic, that is “an infectious disease that spreads to large parts of the world and affects a large proportion of the population of each country”. Today, nobody knows how many will die in this pandemic, or when, or if, we can have a vaccine against the disease.

SARS-CoV-2, or Severe acute respiratory syndrome coronavirus 2, is an RNA virus from the family coronavirus that causes the respiratory disease covid-19.

The virus was detected at the end of last year in the Wuhan sub-province of China, and in most cases causes milder disease symptoms that disappear within two weeks. But sometimes, especially in certain groups such as the elderly and people with certain other underlying illnesses, the infection becomes more severe and can in some cases lead to death.

The virus is believed to have zoonotic origin, that is, it has been transmitted to humans from another animal. Where the origin of the disease comes from, that is to say from which host animal the virus originates, is still unknown. However, the virus has close genetic similarity to a corona virus carried by some bats, which might indicate where the virus comes from.

This model shows the SARS-CoV-2 virus, which causes the illness covid-19. The globe-shaped envelope has a membrane of fat-like substances. Inside the envelope are proteins bound to RNA molecules, that contain the virus’s genes. Short spikes of proteins and longer spikes of glycoprotein stick out of the envelope and attach to receptors on the surface of attacked cells. The spikes, which are bigger at the top, give the virus its appearance reminiscent of the Sun’s corona. This where the coronavirus’s name comes from.

Testing is an important tool for tracking and preventing the spread of infection during an epidemic.

One type of test looks at if a person is infected by looking for traces of the virus’s RNA genetic material. The test is taken using a swab stick inserted into the throat. The small amounts of RNA or DNA that attach to the swab are analyzed using the PCR technique, which was invented by Kary Mullis in 1983. Ten years later he was awarded the Nobel Prize in Chemistry.

Another type of test looks for antibodies to the virus in the blood. This indicates that the person has had the disease.

https://nobelprizemuseum.se/en/coronavirus/

The first virus ever discovered

We have understood since the 19th century that many diseases are caused by microscopic bacteria that cannot be seen by the naked eye. It turned out that there were even smaller contagions: viruses. Research on viruses has been recognized with several Nobel Prizes.

https://nobelprizemuseum.se/en/the-first-virus-ever-discovered/

Spanish flu

The worst pandemic of the 20th century was the Spanish flu, which swept across the world 1918–1920.

The Spanish flu was caused by an influenza virus. American soldiers at military facilities at the end of World War I were likely an important source of its spread in Europe. The war had just ended, and the pandemic claimed even more lives than the war. Between 50 and 100 million people died in the pandemic.

The Red Cross, an international aid organization, which received the Nobel Peace Prize for its efforts during the war, also took part in fighting the Spanish flu. International Committee of the Red Cross received the prize in 1917, 1944 and 1963.

This photo shows personnel from the Red Cross providing transportation for people suffering from the Spanish flu in St. Louis, Missouri in the United States.

https://nobelprizemuseum.se/en/spanish-flu/

Polio

Polio is an illness that often affects children and young people and that can lead to permanent paralysis.

Polio is a highly infectious RNA virus belonging to the genus Enterovirus. The virus only infects humans and enters the body via droplets such as sneezing and coughing, or through contact with infected people’s feces. Usually, polio infects our respiratory and intestinal tract, but sometimes the virus spreads to the spinal cord and can then cause paralysis. The virus mainly affects children, but most of those infected show no or very mild symptoms.

Vaccines are a way to help our immune system fight viruses. The immune system is the body’s defence mechanism against attacks from viruses and bacteria. A number of Nobel Laureates have researched the immune system and contributed to the development of vaccines.

Hepatitis B

The virus can infect people without them becoming sick. Discoveries in the 1960s enabled both vaccines and tests to prevent the spread.

Hepatitis B can infect humans and apes, and is most common in West Africa and in sub-Saharan Africa. The disease also occurs in the rest of Africa, as well as in areas from the Caspian Sea through to China and Korea and further down to Southeast Asia.

Baruch Blumberg discovered the virus behind hepatitis B and developed a vaccine against the disease.

There are many varieties of hepatitis, or jaundice, that cause inflammation in the liver. When studying blood proteins from people from different parts of the world at the end of the 1960s, Baruch Blumberg unexpectedly discovered an infectious agent for hepatitis B. He showed that the infectious agent was linked to a virus of previously unknown type. The virus can infect people without them becoming sick. The discoveries enabled both vaccines and tests to prevent the spread through blood transfusions.

Baruch Blumberg was awarded the Nobel Prize in Physiology or Medicine 1976. He has summarized what the Nobel Prize meant to him.

https://nobelprizemuseum.se/en/hepatitis-b/

Yellow fever

Each year, Yellow fever causes about 30,000 deaths. The vaccine against yellow fever was produced in the 1930s. A work awarded the Nobel Prize.

Yellow fever is a serious disease caused by a virus that is spread by mosquitos in tropical areas of Africa and South America.

Each year, Yellow fever causes about 200,000 infections and 30,000 deaths. About 90% of the cases occur in Africa. The disease is common in warm, tropical climates such as South America and Africa, but it is not found in Asia.

You may think that the number of people infected would be decreasing, but since the 1980s the number of yellow fever cases has unfortunately increased. This is believed to be due to the fact that more and more people are living in cities, that we are traveling more than before, and an increased climate impact.

Since there is no cure for the disease, preventive vaccination is a very important measure. Max Theiler successfully infected mice with a virus in the 1930s, which opened the door to more in-depth studies. When the virus was transferred between mice, a weakened form of the virus was created that gave monkeys immunity. In 1937, Theiler was able to develop an even weaker version of the virus. This version could be used as a vaccine for people.

Max Theiler was awarded the Nobel Prize in Physiology or Medicine in 1951.

https://nobelprizemuseum.se/en/yellow-fever/

HIV/AIDS

In the early 1980s, reports began to emerge about young men that suffered from unusual infections and cancers that normally only affect patients with weakened immune systems. It turned out to be a previously unknown epidemic, HIV, which spread rapidly across the world.

HIV, which is an abbreviation of human immunodeficiency virus, is a sexually transmitted retrovirus that attacks our immune system. An untreated infection eventually leads to AIDS, or acquired immune deficiency syndrome. In 2008, French scientists Luc Montagnier and Françoise Barré-Sinoussi were awarded the Nobel Prize in Physiology or Medicine for the detection of human immunodeficiency virus.

Watch the interview where Françoise Barré-Sinoussi talks about what it is like to meet patients affected by the virus she discovered.

https://nobelprizemuseum.se/en/hiv-aids/

 

Viruses captured in photos

Viruses are incredibly small and cannot be seen in normal microscopes.

The electron microscope, which was invented by Ernst Ruska and Max Knoll in 1933, made it possible to take pictures of much smaller objects than was previously possible. Ernst Ruska’s brother, Helmut Ruska, was a doctor and biologist, and used early electron microscopes to make images of viruses and other small objects. The tobacco mosaic virus was the first virus captured on film. The development of the electron microscope has enabled increasingly better images to be taken.

Ernst Ruska was awarded the 1986 Nobel Prize in Physics together with Gerd Binnig and Heinrich Röhrer, who developed the scanning electron microscope.

Read more about Ernst Ruska – his life and research. https://www.nobelprize.org/prizes/physics/1986/ruska/facts/

https://nobelprizemuseum.se/en/viruses-captured-in-photos/

 

Epidemics and literature

When epidemics and pandemics strike the world, it isn’t just the physical health of people that are impacted but also ways of life, thoughts and feelings. Nobel Laureates in literature have been effected by epidemics and written about life under real and fictive epidemics.

The coronavirus crisis has had a dramatic impact on our lives and our view of our lives. Olga Tokarczuk is one of the authors who has reflected on this.

Tokarczuk argues that the coronavirus has swept away the illusion that we are the masters of creation and that we can do anything since the world belongs to us. She wonders if the pandemic has forced us into a slower, more natural rhythm in life, but also worries about how it may increase distrust of strangers and worsen inequality among people.

Orhan Pamuk has worked for many years on a novel about a bubonic plague epidemic that struck primarily Asia in 1901. The coronavirus crisis has caused him to consider the similarities between the ongoing pandemic and past epidemics throughout history.

He sees several recurring behaviors when epidemics strike: denial and false information, distrust of individuals belonging to other groups, and theories about a malicious intent behind the pandemic. But epidemics also remind us that we are not alone and allow us to rediscover a sense of solidarity. He writes in The New York Times.

https://nobelprizemuseum.se/en/epidemics-and-literature/

Economics Laureates on the current pandemic

Pandemics have wide-ranging impacts on the economy. Paul Romer and Paul Krugman are two economists who have been active in the public discourse during the coronavirus crisis.

Paul Romer has expressed concerns about the pandemic’s effects on the economy but is optimistic about the possibilities of technology. He supports widespread testing. Those who are infected have to stay home for two weeks while others can work and take part in other ways in society.

Paul Romer was awarded the prize “for integrating technological innovations into long-run macroeconomic analysis.” Paul Romer has demonstrated how knowledge can function as a driver of long-term economic growth. He showed how economic forces govern the willingness of firms to produce new ideas.

His thoughts are developed in his lecture during the Nobel Week 2018.

https://nobelprizemuseum.se/en/economics-laureates-on-the-current-pandemic/

 

Other SOURCE

https://www.nobelprize.org/

 

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Study with important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection

Reporter: Aviva Lev-Ari, PhD, RN

Serological Testing WordCloud

Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection

Jeffrey SeowCarl GrahamBlair MerrickSam AcorsKathryn J.A. SteelOliver HemmingsAoife O’BryneNeophytos KouphouSuzanne PickeringRui GalaoGilberto BetancorHarry D WilsonAdrian W SignellHelena WinstoneClaire KerridgeNigel TempertonLuke SnellKaren BisnauthsingAmelia MooreAdrian GreenLauren MartinezBrielle StokesJohanna HoneyAlba Izquierdo-BarrasGill ArbaneAmita PatelLorcan OConnellGeraldine O HaraEithne MacMahonSam DouthwaiteGaia NebbiaRahul BatraRocio Martinez-NunezJonathan D. EdgeworthStuart J.D. NeilMichael H. MalimKatie Doores

Abstract

Antibody (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re-infection. Using sequential serum samples collected up to 94 days post onset of symptoms (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody (nAb) responses when sampled beyond 8 days POS. We demonstrate that the magnitude of the nAb response is dependent upon the disease severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow up period. Whilst some individuals with high peak ID50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID50 had titres approaching baseline within the follow up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy′s and St Thomas′ Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection that causes low disease severity and the circulating seasonal coronaviruses that are associated with common colds. This study has important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection.

SOURCE

https://www.medrxiv.org/content/10.1101/2020.07.09.20148429v1

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How Are Cancer Researchers Fighting COVID-19? Lectures from Koch Institute @MIT

WATCH RECORDING, below

 

Reporter: Aviva Lev-Ari, PhD, RN

  • I attended Jun 29, 2020 11:30 AM Eastern Time the five presentations on

    How Are Cancer Researchers Fighting COVID-19? Lectures from Koch Institute @MIT

 

From: Koch Institute at MIT <no-reply@zoom.us>

Reply-To: <no-reply@zoom.us>

Date: Wednesday, July 1, 2020 at 11:20 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Thank you for attending SOLUTIONS with/in/sight:

How Are Cancer Researchers Fighting COVID-19? (Part II)

 

Hi Aviva Lev-Ari,

Thank you for attending SOLUTIONS with/in/sight: How Are Cancer Researchers Fighting COVID-19? (Part II). We hope you enjoyed our event.

Please submit your questions or comments to: kievents@mit.edu.

You may view a recording of the webinar here: https://ki.mit.edu/news/events/withinsight/jun-2020

Learn more about Koch Institute cancer research and events by signing up for our mailing list here: https://ki.mit.edu/subscribe

Thank you and be safe.

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New Coronavirus Passive Vaccine Developed by Israeli Researchers

Reporter: Irina Robu, PhD

Researchers at Bar-Ilan University have identified short amino acid sequences that could help the development of a vaccine against COVID-19 virus. Of the 25 epitopes that were discovered to be 100% identical to SARS, seven are theoretically efficient vaccine candidates. Their research indicate that they could cover as much as 87% of the world population

Their study has identified a set of immunodominant epitopes from the SARS-CoV-2 proteome, which are capable of generating antibody and cell mediated immune responses. The epitopes, known as antigenic determinants, are the part of the antigen that binds to a specific antigen receptor on the surface of B cells or T cells and are able to provoke an immune response.

It is known that immune response occurs within an organism for the purpose of defending against foreign invaders such as viruses, bacteria, parasites and fungi. The immune responses that are based on specific immunodominant epitopes contain the generation of both antibody- and cell-mediated immunity against pathogens. Such immunity can facilitate fast and effective elimination of the pathogen. The end result is a passive vaccine capable of capable of activating both cellular and humoral immune responses in humans.

According to the team at Bar-Ilan University, the mapped coronavirus epitopes with those of the influenza virus. And they found that 85% of the sequence identity with experimentally detected epitopes of Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV).

Additional analysis indicated that the epitopes are non-allergic and non-toxic to humans and have very low risk for generating autoimmune responses. The team is looking to partner with companies to build vaccine constructs and test them in-vitro and on animal trials before starting any clinical trials.

SOURCE

https://www.jpost.com/health-science/israeli-researchers-on-road-to-new-covid-19-passive-vaccine-630988?utm_source=ActiveCampaign

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The Complexity of Estimation of the Economic Impact of an Outbreak | Panel Discussion | BC Woods College

Reporter: Ofer Markman, PhD

Economic Impact of an Outbreak | Panel Discussion | BC Woods College

197 views

May 21, 2020

Prominent economists, all faculty of the Boston College M.S. in Applied Economics degree program in the Woods College of Advancing Studies, presented a virtual panel discussion on the impact of the coronavirus outbreak on the health care system and the global economy. For more information about the M.S. program, visit https://on.bc.edu/MSAppliedEcon

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COVID-19’s seasonal cycle to be estimated at Lawrence Berkeley National Laboratory (Berkeley Lab) by Artificial Intelligence and Machine Learning Algorithms: Will A Fall and Winter resurgence be Likely??

Reporter: Aviva Lev-Ari, PhD, RN

Using machine learning to estimate COVID-19’s seasonal cycle

Woman walks down empty city street wearing a mask

Credit: Ivan Marc/Shutterstock

Berkeley Lab researchers have launched a project to determine if the novel coronavirus might be seasonal, waning in summer months and resurging in fall and winter.

One of the many unanswered scientific questions about COVID-19 is whether it is seasonal like the flu — waning in warm summer months then resurging in the fall and winter.

Now scientists at Lawrence Berkeley National Laboratory (Berkeley Lab) are launching a project to apply machine-learning methods to a plethora of health and environmental datasets, combined with high-resolution climate models and seasonal forecasts, to tease out the answer.

“Environmental variables, such as temperature, humidity, and UV [ultraviolet radiation] exposure, can have an effect on the virus directly, in terms of its viability. They can also affect the transmission of the virus and the formation of aerosols,” said Berkeley Lab scientist Eoin Brodie, the project lead. “We will use state-of-the-art machine-learning methods to separate the contributions of social factors from the environmental factors to attempt to identify those environmental variables to which disease dynamics are most sensitive.

The research team will take advantage of an abundance of health data available at the county level — such as the severity, distribution and duration of the COVID-19 outbreak, as well as what public health interventions were implemented when — along with demographics, climate and weather factors, and, thanks to smartphone data, population mobility dynamics. The initial goal of the research is to predict — for each county in the United States — how environmental factors influence the transmission of the SARS-CoV-2 virus, which causes COVID-19.

Multidisciplinary team for a complex problem

Untangling environmental factors from social and health factors is a knotty problem with a large number of variables, all interacting in different ways. On top of that, climate and weather affect not only the virus but also human physiology and behavior. For example, people may spend more or less time indoors, depending on the weather; and their immune systems may also change with the seasons.

It’s a complex data problem similar to others tackled by Berkeley Lab’s researchers studying systems like watersheds and agriculture; the challenge involves integrating data across scales to make predictions at the local level. “Downscaling of climate information is something that we routinely do to understand how climate impacts ecosystem processes,” Brodie said. “It involves the same types of variables — temperature, humidity, solar radiation.”

Brodie, deputy director of Berkeley Lab’s Climate and Ecosystem Sciences Division, is leading a cross-disciplinary team of Lab scientists with expertise in climate modeling, data analytics, machine learning, and geospatial analytics. Ben Brown, a computational biologist in Berkeley Lab’s Biosciences Area, is leading the machine-learning analysis. One of their main aims is to understand how climate and weather interact with societal factors.

“We don’t necessarily expect climate to be a massive or dominant effect in and of itself. It’s not going to trump which city shut down when,” Brown said. “But there may be some really important interactions [between the variables]. Looking at New York and California for example, even accounting for the differences between the timing of state-instituted interventions, the death rate in New York may be four times higher than in California — though additional testing on random samples of the population is needed to know for sure. Understanding the environmental interactions may help explain why these patterns appear to be emerging. This is a quintessential problem for machine learning and AI [artificial intelligence].”

The computing work will be conducted at the National Energy Research Scientific Computing Center (NERSC), a DOE Office of Science user facility located at Berkeley Lab.

Signs of climatic influences

map of the worldwide incidence rate of COVID-19
The worldwide incidence rate of COVID-19.
Credit: Center for Systems Science and Engineering at Johns Hopkins University

Already, geographical differences in how the disease behaves have been reported, the researchers point out. Temperature, humidity, and the UV Index have all been statistically associated with rates of COVID-19 transmission — although contact rates are still the dominant influence on the spread of disease. In the southern hemisphere, for example, where it’s currently fall, disease spread has been slower than in the northern hemisphere. “There’s potentially other factors associated with that,” Brodie said. “The question is, when the southern hemisphere moves into winter, will there be an increase in transmission rate, or will fall and winter 2020 lead to a resurgence across the U.S. in the absence of interventions?”

India is another place where COVID-19 does not yet appear to be as virulent. “There are cities where it behaves as if it’s the most infectious disease in recorded history. Then there are cities where it behaves more like influenza,” Brown said. “It is really critical to understand why we see those massive differences.”

Brown notes other experiments suggesting the SARS-CoV-2 virus could be seasonal. In particular, the National Biodefense Analysis and Countermeasures Center (NBACC) assessed the longevity of the virus on various surfaces. “Under sunlight and humidity, they found that the virus loses viability in under 60 minutes,” Brown said. “But in darkness and low temperatures it’s stable for eight days. There’s some really serious differences that need investigating.”

The Berkeley Lab team believes that enough data may now be available to determine what environmental factors may influence the virulence of the virus. “Now we should have enough data from around the world to really make an assessment,” Brown said.

The team hopes to have the first phase of their analysis available by late summer or early fall. The next phase will be to make projections under different scenarios, which could aid in public health decisions.

“We would use models to project forward, with different weather scenarios, different health intervention scenarios — such as continued social distancing or whether there are vaccines or some level of herd immunity — in different parts of the country. For example, we hope to be able to say, if you have kids going back to school under this type of environment, the climate and weather in this zone will influence the potential transmission by this amount,” Brodie explained. “That will be a longer-term task for us to accomplish.”

This research is supported by Berkeley Lab’s Laboratory Directed Research and Development (LDRD) program. Other team members include Dan Feldman, Zhao Hao, Chaincy Kuo, Haruko Wainwright, and Nicola Falco. Berkeley Lab mobilized quickly to provide LDRD funding for several research projects to address the COVID-19 pandemic, including one on text mining scientific literature and another on indoor transmission of the virus.

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COVID-19: Novel Treatment Protocols using Approved drugs vs Standard of Care vs Vaccine and Antiviral new drug discovery and development – An LPBI Group Response and An LPBI Group & Affiliates Response

Curator: Aviva Lev-Ari, PhD, RN

 

On 5/26/2020 LPBI organized a Symposium on New Therapeutics for COVID-19

AGENDA included presentations by:

  • Dr. Raphael Nir, PhD, CSO, SBH, Sciences, Inc. – Drug Concept to mitigate Cytokine Storm in COVID-19 – ATTACHMENT
  • Dr. Ajay Gupta, MD, Professor & Entrepreneur – Rhinitis drug approved in Japan – REPURPOSED for COVID-19 and Application for FDA Approval
  • Dr. Yigal Blum, PhD, ex-SRI Int’l VP and Entrepreneur –  AMORPHOUS CALCIUM CARBONATE (ACC) TREATMENT FOR COVID-19
  • Dr. Orna Harel, PhD, Managing Partner, Agbiopro – Representation for – Prof. Saul Yedgar on the concept and state of preclinical efforts for COVID-19 drug development 
  • Aviva Lev-Ari, PhD, RN – The Potential of REVIVAL of Drug Discovery Initiative and Explorations of Joint Ventures with Biotech companies – An Interim Phase toward POST Coronavirus Pandemic Exit

DISCUSSION – Where and What is the INTERFACE between what our External Relations attempt to accomplish and the Capabilities of LPBI Group’s Team

In the concluding remarks, Dr. Lev-Ari discussed the importance of TREATMENT PROTOCOLS vs. one Therapeutics at a time vs. Combination Drug therapies.

Dr. Lev-Ari pointed the Symposium attendees to the following two points:

1.  The State of Science been endorsed by LPBI Group

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
https://pharmaceuticalintelligence.com/2020/05/23/rna-from-the-sars-cov-2-virus-taking-over-the-cells-it-infects-virulence-pathogens-ability-to-infect-a-resistant-host-the-imbalance-between-controlling-virus-replication-versus-activation-of-the/

2.  LPBI Group’s Position for Treatment Protocol(s)

In continuation to 5/26/2020 Symposium on New Therapeutics for COVID-19, we will follow up with an AGENDA for 6/16/2020 

Part I: Therapeutics for COVID-19

  • Prof. Saul Yedgar – Holder of US Patents on Rhinitis, anti-inflatation and other indications – 40 minutes
  • Dr. Ajay Gupta, MD – Rhinitis drug approved in Japan – FDA Application for Approval of Repurpusing to COVID-19 in the US – 40 minutes
  • Discussion – 20 minutes

 

On 5/29/2020 Dr. Lev-Ari read the article, COVID-19 Critical Care

Analysis by Dr. Joseph Mercola

STORY AT-A-GLANCE

  • Despite the fact that many critical care specialists are using treatment protocols that differ from standard of care, information about natural therapeutics in particular are still being suppressed by the media and is not received by critical care physicians
  • Five critical care physicians have formed the Front Line COVID-19 Critical Care Working Group (FLCCC). The group has developed a highly effective treatment protocol known as MATH+
  • Of the more than 100 hospitalized COVID-19 patients treated with the MATH+ protocol as of mid-April, only two died. Both were in their 80s and had advanced chronic medical conditions
  • The protocols call for the use of intravenous methylprednisolone, vitamin C and subcutaneous heparin within six hours of admission into the hospital, along with high-flow nasal oxygen. Optional additions include thiamine, zinc and vitamin D
  • COVID-19 kills by triggering hyperinflammation, hypercoagulation and hypoxia. The MATH+ protocol addresses these three core pathological processes

COVID-19 Early Intervention Protocol

According to Kory, the FLCCCs MATH+ protocol has been delivered to the White House on four occasions, yet no interest has been shown. Worse, he says they continue to be stonewalled by the U.S. Centers for Disease Control and the National Institute for Health. Why?

Isn’t saving lives, right now, and by any means possible, more important than pushing for a vaccine? If the MATH+ protocol works with near-100% effectiveness, a vaccine may not even be necessary. The MATH+ protocol gets its name from:

Intravenous Methylprednisolone

High-dose intravenous Ascorbic acid

Plus optional treatments Thiamine, zinc and vitamin D

Full dose low molecular weight Heparin

Kory’s testimony transcript reviews and summarizes the MATH+ protocol, and explains why the timing of the treatment is so important. As explained by Kory, there are two distinct yet overlapping phases of COVID-19 infection.

  1. Phase 1 is the viral replication phase. Typically, patients will only experience mild symptoms, if any, during this phase. At this time, it’s important to focus on antiviral therapies.
  2. In Phase 2, the hyperinflammatory immune response sets in, which can result in organ failures (lungs, brain, heart and kidneys). The MATH+ protocol is designed to treat this active phase, but it needs to be administered early enough.

The MATH+ Protocol

The MATH+ protocol7 calls for the use of three medicines, all of which need to be started within six hours of hospital admission:

  • Intravenous methylprednisolone, to suppress the immune system and prevent organ damage from cytokine storms — For mild hypoxia, 40 milligrams (mg) daily until off oxygen; moderate to severe illness, 80 mg bolus followed by 20 mg per day for seven days. On Day 8, switch to oral prednisone and taper down over the next six days.
  • Intravenous ascorbic acid (vitamin C), to control inflammation and prevent the development of leaky blood vessels in the lungs — 3 grams/100 ml every six hours for up to seven days.
  • Subcutaneous heparin (enoxaparin), to thin the blood and prevent blood clots — For mild to moderate illness, 40 mg to 60 mg daily until discharged.

Optional additions include thiamine, zinc and vitamin D. In addition to these medications, the protocol calls for high-flow nasal oxygen to avoid mechanical ventilation, “which itself damages the lungs and is associated with a mortality rate approaching nearly 90% in some centers,” Kory notes.8

Together, this approach addresses the three core pathological processes seen in COVID-19, namely hyperinflammation, hypercoagulability of the blood, and hypoxia (shortness of breath due to low oxygenation).

COVID-19 Should Not Be Treated as ARDS

In the video, Dr. Paul Marik points out that it’s crucial for doctors to treat each patient as an individual case, as COVID-19 is not conventional acute respiratory distress syndrome (ARDS).

If the patient is assumed to have ARDS and placed on a ventilator, you’re likely going to damage their lungs. Indeed, research has now shown that patients placed on mechanical ventilation have far higher mortality rates than patients who are not ventilated. While not discussed here, some doctors are also incorporating hyperbaric oxygen treatment in lieu of ventilation, with great success.

The reason for this is because the primary problem is inflammation, not fluid in the lungs. So, Marik says, they need anti-inflammatory drugs. “It’s not the virus that is hurting the host, it’s the acute inflammatory dysregulated response,” he says. “That’s why you need to use vitamin C and steroids.” He points out that steroids play a crucial role, as it creates synergy with vitamin C.

COVID-19 patients also have a hypercoagulation problem, so they need anticoagulants. In addition to using the proper medication, they must also be treated early. “You have to intervene early and aggressively to prevent them from deteriorating,” Marik says.

Methylprednisolone May Be a Crucial Component

Kory expresses concerns over the fact that health organizations around the world are warning doctors against the use of corticosteroids, calling this a “tragic error”9 as “COVID-19 is a steroid-responsive disease.”10 In his testimony, he points out:11

“Sorin Draghici, CEO of Advaita Bioinformatics, just reported12 that their incredibly sophisticated Artificial Intelligence platform called iPathwayGuide, using cultured human cell lines infected with COVID-19, is able to map all the human genes which are activated by this virus …

Note almost all the activated genes are those that express triggers of inflammation. With this knowledge of the specific COVID inflammatory gene activation combined with knowledge of the gene suppression activity of all known medicines they were able to match the most effective drug for COVID-19 human gene suppression, and that drug is methylprednisolone.

This must be recognized, as the ability of other corticosteroids to control inflammation in COVID-19 was much less impactful. This is, we believe, an absolutely critical and historic finding. Many centers are using similar but less effective agents such as dexamethasone or prednisone.”

As noted by Kory in his senate testimony, Marik, chief of pulmonary and critical care medicine at the Eastern Virginia Medical School in Norfolk, Virginia, is a member of the FLCCC.13 You may recall that Marik was the one who in 2017 announced he had developed an extraordinarily effective treatment against sepsis.

Marik’s sepsis protocol also calls for intravenous vitamin C and a steroid, in this case hydrocortisone, along with thiamine. I for one am not surprised that the two protocols are so similar, seeing how sepsis is also a major cause of death in severe COVID-19 cases.

Safe and Effective Treatments Must Not Be Ignored

As noted by Marik in the video, COVID-19 is not regular ARDS and should not be treated as such. What kills people with COVID-19 is the inflammation, and steroids in combination with vitamin C work synergistically together to control and regulate that inflammation. The heparin, meanwhile, addresses the hypercoagulation that causes blood clots, which is a unique feature of COVID-19. As for the “lack of studies” supporting their protocol, FLCCC notes:14

“A number of official guidelines, such as those of the WHO and several other U.S. agencies, recommend limiting treatment for … critically ill patients to ‘supportive care only’ — and to allow the therapies described here to be studied in randomized controlled trials where half of the patients would receive placebo and where the results would come in months or years.

Our physicians agree that while a randomized controlled trial (RCT), under normal circumstances, might be considered, the early provisions of MATH+, which must be given within hours of critical illness, would inevitably be delayed by such a study design, rendering the validity of the RCT questionable.

Furthermore, while the results of an RCT would not be available for months or more, well-designed observational studies of the protocol could yield timely feedback during this pandemic, to improve the treatment process much more quickly.”

I believe this information needs to be shared far and wide, if we are to prevent more people from dying unnecessarily. More and more, as doctors are starting to speak openly about their clinical findings, we’re seeing that there are quite a few different ways to tackle this illness without novel antivirals or vaccines, using older, inexpensive and readily available medications that are already known to be safe.

References

SOURCE

https://blogs.mercola.com/sites/vitalvotes/archive/2020/05/28/lab-escape-theory-of-sarscov2-origin-gaining-scientific-support.aspx

 

A Response by LPBI Group and a Potential Response by LPBI Group and its Affiliates

 

LPBI Group’s Components in Novel Treatment Protocol Definition

 

  • Forthcoming by Stephen J. Williams, PhD – Immuno-theraphy boosting Protocol

based on

T cells found in COVID-19 patients ‘bode well’ for long-term immunity | Science | AAAS
https://www.sciencemag.org/news/2020/05/t-cells-found-covid-19-patients-bode-well-long-term-immunity

 

  • Forthcoming by Aviva Lev-Ari, PhD, RN and Stephen J. Williams, PhD – Nitric Oxide Inhaler OR Bystolic® (nebivolol) www.bystolicpro.com
  • Two alternatives per stage of COVID-19 infections: Severe or Moderate

based on

 

  • LPBI Group’s Affiliates:

If you wish your Therapeutic solution to be included in the NEW DEFINITION of Treatment Protocol(s), then propose your component for inclusion in the Novel Treatment Protocol to be discussed on June 16, 2020

LPBI Group’s Affiliates Components in the Novel Treatment Protocol(s) Definition

  • Prof. Saul Yedgar – Holder of US Patents on Rhinitis, anti-inflammation and other indications – 40 minutes
  • Dr. Ajay Gupta, MD – Rhinitis drug approved in Japan – FDA Application for Approval of Repurposing to COVID-19 in the US – 40 minutes
  • Dr. Raphael Nir, PhD, CSO, SBH, Sciences, Inc. – Drug Concept to mitigate Cytokine Storm in COVID-19 
  • Dr. Yigal Blum, PhD, ex-SRI Int’l VP and Entrepreneur –  AMORPHOUS CALCIUM CARBONATE (ACC) TREATMENT FOR COVID-19

References on Nitric Oxide on PharmaceuticalIntellige.com – Open Access Online Scientific Journal include 299 articles

https://pharmaceuticalintelligence.com/?s=Nitric+Oxide

Of note

 

Included in the 299 articles

  • Transposon-mediated Gene Therapy improves Pulmonary Hemodynamics and attenuates Right Ventricular Hypertrophy: eNOS gene therapy reduces Pulmonary vascular remodeling and Arterial wall hyperplasia

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/31/transposon-mediated-gene-therapy-improves-pulmonary-hemodynamics-and-attenuates-right-ventricular-hypertrophy-enos-gene-therapy-reduces-pulmonary-vascular-remodeling-and-arterial-wall-hyperplasia/

 

Author and Curator of an Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

 

  • Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production,  stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

Curator of an Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/

 

  • Cardiovascular Disease (CVD) and the Role of Agent Alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Curator and Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

 

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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

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 vitroex 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

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 KonnoIzumi KimuraKeiya UriuMasaya FukushiTakashi IrieYoshio KoyanagiSo NakagawaKei Sato

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

 

 

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.

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