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Ebola therapy breakthrough

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Updated 11/23/2015

Giant Molecules Inhibit Ebola Infection

Nov 11, 2015   http://www.technologynetworks.com/medchem/news.aspx?ID=185080

European researchers have designed a “giant” molecule formed by thirteen fullerenes covered by carbohydrates which, by blocking this receptor, are able to inhibit the cell infection by an artificial ebola virus model.

 

Different studies have demonstrated that the ebola virus infection process starts when the virus reaches the cellular DC-SIGN receptor to infect the dendritic cells (of the immune system).

In this study researchers from the Universidad Complutense de Madrid/IMDEA-Nanociencia, the Instituto de Investigación Sanitaria Hospital 12 de Octubre (Madrid), and the Instituto de Investigaciones Químicas del CSIC-Universidad de Sevilla have collaborated, together with three european research groups (CNRS/Université de Strasbourg, France and Université de Namur, Belgium).

“Fullerenes are hollow cages exclusively formed by carbon atoms”, explains Nazario Martín, Professor of Organic Chemistry in the UCM and main author of the study. In this work, scientists have employed C60 fullerene, which is formed by 60 carbon atoms and has the shape of a truncated icosahedron, which resembles a football ball.

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These molecules decorated with specific carbohydrates (sugars) present affinity by the receptor used as an entry point to infect the cell and act blocking it, thus inhibiting the infection.

Researchers employed an artificial ebola virus by expressing one of its proteins, envelope protein GP1, responsible of its entry in the cells. In a model in vitro, this protein is covering a false virus, which is able of cell infection but not of replication.

“We have employed a cell model previously described in our lab which consists in a cell line of human lymphocytes expressing DC-SIGN receptor, which facilitates the entry of the virus in Dendritic Cells”, points out Rafael Delgado, researcher of the Hospital 12 de Octubre, and other of the authors of the study.

By blocking this receptor and inhibiting the virus infection, the authors think that the dissemination of the virus would decrease and the immune response increase, but this idea has still to be developed with in vivo studies.

The biggest fullerene system in the lab

The system designed by the chemists, based on carbon nanostructures developed in the UCM, mimic the presentation of carbohydrates surrounding virus like ebola or VIH.

The team has achieved an unprecedented success in fullerene chemistry and dendritic growth: connecting in one synthetic step twelve fullerene units, each with ten sugars, to other central fullerene, creating a globular superstructure with 120 sugar moieties on its surface, “this is the fastest dendrimeric growth developed in a laboratory up to now” says Beatriz Illescas, Professor in the UCM and coauthor of the work.

According to scientists, the results highlight the potential of these giant molecules as antiviral agents. “This work open the door to the design and preparation of new systems to inhibit the pathogens infection in cases where the current therapies are not effective or are inexistent, as occurs with the ebola virus”, clarifies Martín.

After these experiments on the cellular level, researchers will study the behavior of these systems in animal models, starting with mice. “We will study, on the one hand, the pharmacokinetics and, on the other, the antiviral activity in vivo” explains Javier Rojo, researcher of the Instituto de Investigaciones Químicas del CSIC and other of the authors of the study. Once the most effective compound has been identified, studies using the true ebola virus could be carried out.

 

 

http://www.sciencedirect.com/science/article/pii/S0092867400806935

DCSIGN, which is abundantly expressed by DC both in vitro and in vivo, … Whereas ICAM-3 binding by monocytes is for the greater part LFA-1 … The specificity of this adhesion receptor on DC for ICAM-3 is demonstrated by the ….

 

http://www.bloodjournal.org/content/100/5/1780.full.pdf

This subset coexpresses CD14, CD16, and CD33 and is thus of myeloid origin. In contrast to. CD14 monocytes, DCSIGN blood cells.

 

http://www.jimmunol.org/content/168/5/2118.full

Mar 1, 2002 Several receptors expressed by immature DCs belong to the C-type lectin superfamily, … Here, DCSIGN efficiently transmits the virus to T lymphocytes

 

http://journals.plos.org/plospathogens/article%3Fid%3D10.1371/journal.ppat.0020070

Jul 14, 2006 Although B cells that express DCSIGN do not replicate HIV-1, they serve as … receptors [12–15], with conflicting reports on expression of DCSIGN[16,17]. …..
human herpesvirus 8 infects DC and macrophages via DCSIGN …

 

http://www.jci.org/articles/view/25105/files/pdf

Results. The effect of human milk on direct HIV-1 infection of CD4+ T lymphocytesexpressing the DCSIGN receptor (Raji-DCSIGN) (8).

 

 

An indictment of Ebola response  

Panel calls for reform of global public health system in wake of epidemic

By B. D. Colen, Harvard Staff Writer

http://news.harvard.edu/gazette/story/2015/11/an-indictment-of-ebola-response/

 

http://media.news.harvard.edu/gazette/wp-content/uploads/2015/11/110515_Ebola_020_605.jpg

“The most egregious failure was by WHO in the delay in sounding the alarm,” said Harvard’s Ashish Jha.

An independent group of 19 international experts, convened by theHarvard Global Health Institute and the London School of Hygiene and Tropical Medicine (LSHTM), today issued a scathing analysis of the global response to the 2014-15 Ebola outbreak in West Africa.

The members of the Harvard-LSHTM Independent Panel on the Global Response to Ebola said that while the 2014-15 Ebola outbreak “engendered acts of understanding, courage, and solidarity,” it also caused “immense human suffering, fear and chaos, largely unchecked by high-level political leadership or reliable and rapid institutional responses.”

The report, published in the prestigious British medical journal The Lancet, is especially hard on the World Health Organization (WHO), which the panel contends failed to provide the leadership and support needed to deal properly with the outbreak of hemorrhagic fever that infected more than 28,000 people and claimed more than 11,000 lives.

The authors of the report, who were affiliated with, but functioned independently from, such disparate organizations as the Council on Foreign Relations, Médecins Sans Frontières, Indiana University law school, and theAIDS Health Care Foundation, reminded readers that the Ebola epidemic “brought national health systems to their knees, rolled back hard-won social and economic gains in a region recovering from civil wars, sparked worldwide panic, and cost at least several billion dollars in short-term control efforts and economic losses.”

“The most egregious failure was by WHO in the delay in sounding the alarm,” said Ashish Jha, director of the Harvard Global Health Institute, K.T. Li Professor of International Health at the Harvard T.H. Chan School of Public Health, and a professor of medicine at Harvard Medical School. “People at WHO were aware that there was an Ebola outbreak that was getting out of control by spring … and it took until August to declare a public health emergency … Those were precious months,” said Jha.

The panel was co-chaired by Professor Peter Piot, director of the LSHTM and co-discoverer of the Ebola virus. Piot said, “We need to strengthen core capacities in all countries to detect, report, and respond rapidly to small outbreaks, in order to prevent them from becoming large-scale emergencies. Major reform of national and global systems to respond to epidemics are not only feasible, but also essential so that we do not witness such depths of suffering, death, and social and economic havoc in future epidemics. The AIDS pandemic put global health on the world’s agenda. The Ebola crisis in West Africa should now be an equal game-changer for how the world prevents and responds to epidemics.”

Liberian Mosoka Fallah of Action Contre la Faim International and a member of the panel said, “The human misery and deaths from the Ebola epidemic in West Africa demand a team of independent thinkers to serve as a mirror of reflection on how and why the global response to the greatest Ebola calamity in human history was late, feeble, and uncoordinated. The threat of infectious disease anywhere is the threat of infectious disease everywhere. The world has become one big village.”

The global response to Ebola is being examined by a number of different panels, Jha said, including a group at WHO and another at the United Nations. During the height of the epidemic in fall, 2014, Jha met with Julio Frenk, then the dean of the Harvard Chan School, and Suerie Moon, research director and co-chair of the Harvard Kennedy School’s Forum on Global Governance for Health, and a Harvard Chan faculty member. Together, they “decided this deserves independent examination; we can’t let this happen again,” Jha said.

“The Ebola outbreak is a stark reminder of the fragility of health security in an interdependent word,” the report reads, “and of the importance of building a more robust global system to protect all people from such risks.

“A more humane, competent, and timely response to future outbreaks requires greater willingness to assist affected populations, and systematic investments to enable the global community to perform four key functions: strengthen core capacities within and among countries to prevent, detect, and respond to outbreaks when and where they occur; mobilize faster and more effective external assistance when countries are unable to prevent an outbreak from turning into a crisis alone; rapidly produce and widely share relevant knowledge, from community mobilization strategies to protective measures for health workers, from rapid diagnostic tools to vaccines; [and] provide stewardship over the whole system, entailing strong leadership, coordination, priority setting, and robust accountability from all involved actors.”

Though it pulls no punches in its criticism of the ways institutions and nations responded to the Ebola crisis, the Harvard-LSHTM report is also a positive document, offering 10 concrete recommendations to strengthen public health systems and future responses.

Those recommendations fall into four areas: preventing major disease outbreaks; responding to outbreaks; producing and sharing data, knowledge, and technologies; and improving the governance of the global health system, “with a focus on the World Health Organization.”

One recommendation is that WHO create a dedicated center “for outbreak response, with strong technical capacity, protected budget, and clear lines of accountability,” and that that center be governed by a separate board independent of the WHO bureaucracy.

“Our primary goal is to convince the high-level political leaders, north and south, to seize the moment to make necessary and enduring changes to better prepare for future outbreaks, while memories of the human health costs of inaction remain vivid and fresh,” the report said.

“There is a high risk here of not learning our lessons,” said Jha. “We’ve had outbreaks like this before, and often you get thoughtful reviews, and august bodies that look at it, and people say, ‘We will get to this right away,’ and then other things draw our attention. I think we owe it to the more than 11,000 people who died in West Africa to see that that doesn’t happen this time.”

 

The Lancet 2015

http://www.thelancet.com/campaigns/ebola

Ebola—lessons learned: Authors from Harvard’s Global Health Institute and the London School of Hygiene and Tropical Medicine outline 10 proposals to help prevent future health catastrophes, based on experiences from the 2014-15 Ebola outbreak in west Africa.

Timeline infographic

Illustration demonstrating pathogenesis of vascular leak in Ebola virus disease - Copyright: Elsevier
http://www.thelancet.com/pb/assets/raw/pb/assets/raw/lancet/campaigns/ebola/ebola-main-281114.jpg

The current outbreak of Ebola in west Africa is both a public health emergency of international concern and a human tragedy.

The Lancet Ebola Resource Centre contains all related resources from The Lancet family of journals offered with free access to assist health workers and researchers in their important work to bring this outbreak to a close a quickly as possible.

Find out more about Ebola in The Lancet’s Seminar.

 

WORLD REPORT
Expert panel slams WHO’s poor showing against Ebola
John Maurice
The Lancet, July 13, 2015;Vol. 386, No. 9990, e1

Criticism of WHO’s response to the west African Ebola crisis spawned an expert review that this week proposed several solutions to restore the agency’s performance. John Maurice reports.

WHO suffers from an incapacity “to deliver a full emergency public health response” against a severe epidemic. So concluded a panel of six international health experts in a damning report released on July 7. They prescribed 21 actions aimed at restoring WHO’s “pre-eminence as the guardian of global public health”.

The panel was commissioned by WHO Director-General Margaret Chan in response to widespread criticism that WHO had mishandled its response to the west African Ebola epidemic. The panel corroborated many of the criticisms. Chief among them was the “unjustifiable” time it took WHO to declare the outbreak a “public health emergency of international concern”. Chan made this declaration 5 months after the escalating spread of Ebola had become evident. WHO officials claim that the delay in making the official declaration did not affect its operations involving some 100 staff in the field in the early months of the epidemic.

WHO’s Member States also drew sharp criticism from the panel. Many applied travel bans during the epidemic without WHO authorisation, thereby contravening the International Health Regulations (IHR) and “causing negative political, economic and social consequences for the affected countries”. Perhaps the most damning criticism of WHO came from Médecins sans Frontières (MSF), whose teams were among the first to arrive at the scene of the outbreak in March, 2014. An MSF reportpublished in March, 2015, describes how MSF was unable to convince WHO that the epidemic was out of control. “WHO officials”, the report notes, “called us alarmists”.

Four of the panel’s recommendations stand out: countries should be given incentives to comply with the IHR and disincentives, such as sanctions, when they flout them; a brand-new WHO Centre for Emergency Preparedness and Response should be created; a contingency fund of US$100 million to be used solely to finance outbreak responses should be established; and an intermediate trigger should be set up to alert the health community to a health crisis before it becomes an emergency.

Asked whether the panel’s report meets her concerns, MSF president Joanne Liu tells The Lancet: “It has many strong points for us. But how they will translate into real action on the ground” is unclear. Liu is particularly pleased with the panel’s call for greater community engagement in epidemic response efforts. “As regards an intermediate alert”, she says, “it should be based on the needs of the affected communities, not just on a perceived security risk for other countries. MSF didn’t wait for an official declaration before going into the field.”

David Heymann, head and senior fellow at the Centre on Global Health Security in Chatham House, London, wonders whether the panel’s recommendations for fundamental changes in the decision-making processes can be implemented. “WHO has a flawed structure and I’m not sure its Member States have the will to change that.” He commends the panel’s call for strengthening existing emergency response mechanisms, such as the Global Outbreak Alert and Response Network (GOARN). “This is an agile, sustainable network of epidemiologists, logisticians, and other field-support experts from WHO Member States. It goes immediately into action to prevent outbreaks from becoming emergencies of international concern and has worked extremely well in previous Ebola outbreaks and in the 2003 SARS epidemic.” He believes that the existence of GOARN, with an added external advisory group, obviates the need for the new WHO emergency response centre proposed by the panel.

Will WHO implement the recommendations? “If it doesn’t implement them now”, says Jeremy Farrar, director of the Wellcome Trust, “it will never do so, because the Ebola epidemic has really shocked people and has exposed the structural weaknesses in WHO. Reforming its emergency response capabilities means reducing the bureaucracy and speeding up its capacity to respond. And that means appointing the very best people.” Farrar is enthusiastic about the proposed creation of a new WHO emergency response body. “It should be overseen by an independent board and needs to be outside the influence of politics and truly independent. It also needs to be given the right authority, the right budget, and the right mandate in order to attract the right leadership.”

Rick Brennan, director of WHO’s emergency operations, found the panel’s report constructive. “Work has already begun on several of the recommendations, such as increasing staff and funds for emergency operations and integrating our health security and humanitarian work. I’m convinced that we will implement the rest of the recommendations, including the creation of a new WHO health emergency centre.”

Experts were unanimous on one point made in the report. With 20–30 cases occurring every week, Ebola in west Africa is not over and many eyes are now on WHO’s role in ending it.

EDITORIAL
A plan to protect the world—and save WHO
The Lancet July 11, 2015
The Lancet, Vol. 386, No. 9989, p103

“WHO must reestablish its pre-eminence as the guardian of global public health.” These words resonate throughout the final report of the Ebola Interim Assessment Panel, requested by WHO’s Executive Board, chaired by Dame Barbara Stocking, and published this week. The findings of the panel present a devastating critique of WHO and the chronic inaction of its member states, which together created the conditions for an Ebola virus disease outbreak of unprecedented ferocity and human tragedy. The Stocking Report, as it will come to be known, sets out in agonising detail how the entire global health system fatally let down the people of west Africa.

Stocking reserves her harshest criticism for WHO. The delays in announcing a Public Health Emergency of International Concern (it took 5 months from announcing an “unprecedented outbreak” in April, 2014, to declaring a public health emergency on August 8) was “unjustifiable”. The agency’s culture is unfit to manage an emergency response. Independent and courageous decision-making by the Director-General of WHO and her team “was absent in the early months of the Ebola crisis”. The agency was slow and reactive to events. WHO has lost its position as the authoritative body on health emergencies. It thought it could manage Ebola through polite behind-the-scenes international diplomacy. It failed to recognise that Ebola was a health emergency, not a diplomatic puzzle. And WHO’s communication strategy for Ebola simply “failed”. The agency failed to communicate proactively and it failed to establish itself as the authoritative voice on the Ebola outbreak. Member States of WHO are not spared. They have persistently failed to take the International Health Regulations (IHR, 2005) seriously—a position that is “irresponsible” and “untenable” for global health security. They should adopt the notion of “shared sovereignty”. They need to invest in WHO (the Panel proposes a modest 5% increase in assessed contributions in 2016).

The Panel’s recommendations are clear and forthright. Although WHO was severely criticised, Stocking argues that the agency should still take the lead for emergency health responses. But to do so, WHO must undergo “significant transformation”—not least, adequate funding and a change in culture. It must provide costed plans for establishing core public health capacities as set out in the IHR (2005). It should establish a new WHO Centre for Emergency Preparedness and Response, with an independent board that publishes a report on Global Health Security annually. WHO country and regional offices should be strengthened. The agency should take its role in accelerating the research and development of diagnostics, vaccines, and medicines more seriously. And WHO should do more to coordinate its activities with other parts of the humanitarian community. The IHR Review Committee should examine the value of an intermediate alert for a public health emergency, lowering the threshold at which the world can be warned of a new health risk. And sanctions against countries that violate the IHR should be considered.

The Panel makes clear that global health must be put at the centre of the global security agenda. But while its recommendations are cogent, there are three important omissions that deserve attention. First, the Panel does not address the vicious cycle within which WHO is caught. The reason why WHO is so poorly resourced is that it lacks the confidence of donors. As the agency continues to underperform because of chronic underinvestment, so that lack of confidence (and the resultant unwillingness to invest) only worsens. The Panel presents no way out of this endless circle of failure. Second, one of the most important responsibilities for governments is the preservation of public order and national security. In the context of Ebola (indeed, any health crisis), this means creating resilient health systems to protect populations from unexpected shocks, as explained by Mosoka Fallah and colleagues in a letter from Liberia’s Ministry of Health this week. Universal health coverage should have been emphasised as a crucial instrument in building global health security. Finally, the Panel rightly notes that, “While WHO has already accepted the need for transformation of its organisational culture and delivery, it will need to be held accountable to ensure that this transformation is achieved”. However, nowhere does the Panel recommend the accountability mechanism to monitor and review the implementation of its recommendations. Our fear is that the unique opportunity presented by the Stocking Report will be squandered. We have little confidence that the governing bodies of WHO will deliver on the expectations of Stocking and her team. The responsibility for action therefore falls to WHO’s Director-General. Dr Margaret Chan has 20 months to save her agency from further and possibly irreversible reputational damage.

ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study
Mara Jana Broadhurst, John Daniel Kelly, Ann Miller, Amanda Semper, Daniel Bailey, et al.

The Lancet, June 25, 2015; Vol. 386, No. 9996, p867–874    http://dx.doi.org/10.1016/S0140-6736(15)61042-X    
Background  At present, diagnosis of Ebola virus disease requires transport of venepuncture blood to field biocontainment laboratories for testing by real-time RT-PCR, resulting in delays that complicate patient care and infection control efforts. Therefore, an urgent need exists for a point-of-care rapid diagnostic test for this disease. In this Article, we report the results of a field validation of the Corgenix ReEBOV Antigen Rapid Test kit.
Methods   We performed the rapid diagnostic test on fingerstick blood samples from 106 individuals with suspected Ebola virus disease presenting at two clinical centres in Sierra Leone. Adults and children who were able to provide verbal consent or assent were included; we excluded patients with haemodynamic instability and those who were unable to cooperate with fingerstick or venous blood draw. Two independent readers scored each rapid diagnostic test, with any disagreements resolved by a third. We compared point-of-care rapid diagnostic test results with clinical real-time RT-PCR results (RealStar Filovirus Screen RT-PCR kit 1·0; altona Diagnostics GmbH, Hamburg, Germany) for venepuncture plasma samples tested in a Public Health England field reference laboratory (Port Loko, Sierra Leone). Separately, we performed the rapid diagnostic test (on whole blood) and real-time RT-PCR (on plasma) on 284 specimens in the reference laboratory, which were submitted to the laboratory for testing from many clinical sites in Sierra Leone, including our two clinical centres.
Findings   In point-of-care testing, all 28 patients who tested positive for Ebola virus disease by RT-PCR were also positive by fingerstick rapid diagnostic test (sensitivity 100% [95% CI 87·7–100]), and 71 of 77 patients who tested negative by RT-PCR were also negative by the rapid diagnostic test (specificity 92·2% [95% CI 83·8–97·1]). In laboratory testing, all 45 specimens that tested positive by RT-PCR were also positive by the rapid diagnostic test (sensitivity 100% [95% CI 92·1–100]), and 214 of 232 specimens that tested negative by RT-PCR were also negative by the rapid diagnostic test (specificity 92·2% [88·0–95·3]). The two independent readers agreed about 95·2% of point-of-care and 98·6% of reference laboratory rapid diagnostic test results. Cycle threshold values ranged from 15·9 to 26·3 (mean 22·6 [SD 2·6]) for the PCR-positive point-of-care cohort and from 17·5 to 26·3 (mean 21·5 [2·7]) for the reference laboratory cohort. Six of 16 banked plasma samples from rapid diagnostic test-positive and altona-negative patients were positive by an alternative real-time RT-PCR assay (the Trombley assay); three (17%) of 18 samples from individuals who were negative by both the rapid diagnostic test and altona test were also positive by Trombley.
Interpretation   The ReEBOV rapid diagnostic test had 100% sensitivity and 92% specificity in both point-of-care and reference laboratory testing in this population (maximum cycle threshold 26·3). With two independent readers, the test detected all patients who were positive for Ebola virus by altona real-time RT-PCR; however, this benchmark itself had imperfect sensitivity.
Malaria morbidity and mortality in Ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis
Patrick G T Walker, Michael T White, Jamie T Griffin, Alison Reynolds, Neil M Ferguson, Azra C Ghani
The Lancet Infectious Diseases, April 23, 2015; Vol. 15, No. 7, p825–832  http://dx.doi.org/10.1016/S1473-3099(15)70124-6    
Background  The ongoing Ebola epidemic in parts of west Africa largely overwhelmed health-care systems in 2014, making adequate care for malaria impossible and threatening the gains in malaria control achieved over the past decade. We quantified this additional indirect burden of Ebola virus disease.
Methods  We estimated the number of cases and deaths from malaria in Guinea, Liberia, and Sierra Leone from Demographic and Health Surveys data for malaria prevalence and coverage of malaria interventions before the Ebola outbreak. We then removed the effect of treatment and hospital care to estimate additional cases and deaths from malaria caused by reduced health-care capacity and potential disruption of delivery of insecticide-treated bednets. We modelled the potential effect of emergency mass drug administration in affected areas on malaria cases and health-care demand.
Findings  If malaria care ceased as a result of the Ebola epidemic, untreated cases of malaria would have increased by 45% (95% credible interval 43–49) in Guinea, 88% (83–93) in Sierra Leone, and 140% (135–147) in Liberia in 2014. This increase is equivalent to 3·5 million (95% credible interval 2·6 million to 4·9 million) additional untreated cases, with 10 900 (5700–21 400) additional malaria-attributable deaths. Mass drug administration and distribution of insecticide-treated bednets timed to coincide with the 2015 malaria transmission season could largely mitigate the effect of Ebola virus disease on malaria.
Interpretation  These findings suggest that untreated malaria cases as a result of reduced health-care capacity probably contributed substantially to the morbidity caused by the Ebola crisis. Mass drug administration can be an effective means to mitigate this burden and reduce the number of non-Ebola fever cases within health systems.

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