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Culprit Mutations, Risky (Neandertal) Variants, Genomic Analysis App: COVID-19 Updates



October 2, 2020 | Genetic variations not driving outcomes, bio-sensing viral translation, pursuit of a passive vaccine, an Android app that analyzes the SARS-CoV-2 genome, potential antibody cocktails, targeting the hairpin, spike protein may be superantigen, implicating MAIT cells, three mutations common to COVID cases in the U.S., naturally occurring lipid and enzyme hold promise, research using breathing human lungs cells, widespread preexisting immunity, and a Neandertal gene variant that triples the risk of severe disease. Plus, an interactive exhibition about COVID-19 and an international team of experts will study how viral diseases "spill over" from animals to humans.

 

Research Updates  

A comprehensive search of genetic variation databases has revealed no significant differences across populations and ethnic groups in seven genes associated with viral entry of SARS-CoV-2, according to a study published in Infection, Genetics and Evolution. Researchers from Boston Children’s Hospital and Hokkaido University (Japan) surveyed publicly available databases of genomic variants, including gnomAD, the Korean Reference Genome Database, TogoVar (a Japanese genetic variation database) and the 1000 Genomes Project. Genetic variants were found in each of the seven implicated proteins, the largest number in the ACE2 receptor on the cell surface, but very few of the variations altered the functions of the proteins. The overall variation frequency was also extremely low (less than 0.01%). Findings suggest that differences in COVID-19 morbidity and mortality are not the result of genetic variations across populations but more likely due to preexisting medical conditions, individual medical histories, environmental factors and healthcare disparities. DOI: 10.1016/j.meegid.2020.104507

Researchers from the University of Montpellier (France) and Princeton University report in Proceedings of the National Academy of Sciences that air emitted during plosive speech sounds (e.g. “P”) forms vortical puffs that travel out approximately one meter. Speech containing a train of such puffs forms a continuous, turbulent, jet-like flow capable of transporting exhaled air and droplets out to two meters or more during 30 seconds of conversation. The information could inform public health strategies for mitigating airborne disease transmission, the authors say. DOI: 10.1073/pnas.2012156117

At Colorado State University, scientists have has shown an important mechanism in the host-attacking process of infectious viruses at the single-molecule level in living cells and have reproduced these behaviors in computational models. Their experiments and models, published in Nature Structural and Molecular Biology, reveal in unprecedented detail how viruses initiate translation of genetic material into proteins. Researchers invented a biosensor that lights up blue when viral translation is happening, and green when normal host translation is happening, allowing differentiation between normal and viral host processes in real time. The biosensor also permits the effects of different types of stress that cells undergo when being attacked by a virus to be visualized, and how, where and when normal versus viral translation increase or decrease. In cells under stress, internal ribosome entry sites (IRES) translation dominates. Although SARS-CoV-2 does not contain IRES, the biosensor is modular and can easily incorporate pieces of the virus to explore how it uniquely hijacks host replication machinery during infection. DOI: 10.1038/s41594-020-0504-7  

Researchers at the German Center for Neurodegenerative Diseases (DZNE) and Charité - Universitätsmedizin Berlin have identified highly effective antibodies against SARS-CoV-2 and are now pursuing the development of a passive vaccine. Thye have also discovered that some SARS-CoV-2 antibodies bind to tissue samples from the brain, heart muscle and blood vessels, which could potentially trigger undesired side effects. Their findings are reported in Cell. The scientists isolated almost 600 different antibodies from the blood of individuals who had overcome COVID-19 and then narrowed this number down to a few that were particularly effective at binding to the virus. Next, they produced these neutralizing antibodies artificially using cell cultures. Studies in hamsters confirmed the high efficacy of the selected antibodies. Development of a passive vaccine, focused on three antibodies that look particularly promising for clinical development, is now underway via a collaboration with Germany-based global biotechnology company Miltenyi Biotec. Planning has already started for clinical trials, although none are expected to begin any earlier than the end of this year.  DOI: 10.1016/j.cell.2020.09.049  

A new mobile app Genopo—developed by the Garvan Institute of Medical Research (Australia) in collaboration with the University of Peradeniya (Sri Lanka)—has made it possible to analyze the genome of the SARS-CoV-2 virus on a smartphone in less than half an hour. This makes genomics more accessible to remote or under-resourced regions, as well as the hospital bedside. Until now, genomic analysis has required the processing power of high-end server computers or cloud services. The new app could execute bioinformatics workflows on nanopore sequencing datasets that are downloaded to a smartphone and combines several “miniaturized” versions of available bioinformatics tools that work on the processing power of a consumer Android device. Researchers tested their app on different Android devices, including models from Nokia, Huawei, LG and Sony. The app is a free, open-source application available through the Google Play store and described in Communications Biology. DOI: 10.1038/s42003-020-01270-z

As reported in Science, an international team of researchers has shown that a mix of ultrapotent antibodies from recovered COVID-19 patients can recognize and lock down the infection machinery of the pandemic coronavirus and keep it from entering cells. Each of the antibody types performs these overlapping tasks slightly differently. Low doses of these antibodies, individually or as a cocktail, were also shown to protect hamsters from infection when exposed to the coronavirus by preventing it from replicating in their lungs. The presence of the antibodies additionally seems to set off the infection-fighting actions of other immune cells that arrive to clear out the virus. Besides directly preventing interactions with the host receptor, one of two discovered antibodies prevented the virus from fusing with the host membrane on the surface of the cell. Findings could pave the way to implement antibody cocktails for prophylaxis or therapy that might have the advantage of circumventing or limiting the emergence of viral escape mutants. DOI: 10.1126/science.abe3354  

Small molecules that target a structure within the RNA genome of SARS-CoV-2, interfering with viral gene expression and targeting the RNA for destruction, have been identified by researchers from The Scripps Research Institute and Iowa State University. The so-called frameshifting element of the RNA contains a hairpin that helps the virus translate its genes into proteins, and the team found a molecule—compound 5 (C5)—which decreases the hairpin's efficiency in doing its job by about 25% in cell culture experiments. To enhance the potency of C5, they attached a molecule called a ribonuclease-targeting chimera (RIBOTAC) that recruits a human enzyme to degrade the viral RNA. In cultured cells, RIBOTAC increased the potency of C5 by about 10-fold. Study findings appear in ACS Central Science.  DOI: 10.1021/acscentsci.0c00984

Researchers at the University of Pittsburgh School of Medicine and Cedars-Sinai identified a putative T-cell receptor binding motif in the SARS-CoV-2 spike protein that is absent from other beta-coronaviruses, the sequence and structure of which resemble a bacterial superantigenic peptide that causes toxic shock syndrome. COVID-19 patients with severe hyperinflammation exhibited a T cell receptor repertoire distinct from that of patients with mild/moderate disease, suggesting that the SARS-CoV-2 spike may act as a superantigen to cause multisystem inflammatory syndrome in children and cytokine storm in adults. The study published in Proceedings of the National Acadamy of Sciences. DOI: 10.1073/pnas.2010722117

Mucosa-associated invariant T (MAIT) cells, which account for a small fraction of T cells in the blood of healthy people, are strongly activated in people with moderate to severe COVID-19 disease, according to a study by researchers at Karolinska Institute (Sweden) that published in Science Immunology. MIAT cells are primarily important for controlling bacteria but can also be recruited by the immune system to fight some viral infections. Study results indicate that the number of MAIT cells in the blood of 24 patients with moderate to severe COVID-19 disease sharply decline and the remaining cells in circulation are highly activated—suggesting they are engaged in the immune response against SARS-CoV-2. Pro-inflammatory MAIT cells also accumulated in the airways of COVID-19 patients to a larger degree than in healthy people (14 individuals), which partly explains the reduced number of MAIT cells in their blood. In convalescent patients (45 individuals), the number of MAIT cells in the blood recovered at least partially in the weeks after disease and, among four patients who had died, the MAIT cells tended to be extremely activated with lower expression of the receptor CXCR3 than in those who survived. DOI: 10.1126/sciimmunol.abe1670

Researchers in China have identified potential therapeutic effects of the anticoagulation agent dipyridamole in the severely ill patients with COVID-19. In an analysis of a randomly collected cohort of 124 patients with COVID-19, the authors found that hypercoagulability (as indicated by elevated concentrations of D-dimers) was associated with disease severity. By virtual screening of an FDA-approved drug library, they identified dipyridamole in silico, which suppressed SARS-CoV-2 replication in vitro. The original research, available online since April, appears in a recent special issue of Acta Pharmaceutica Sinica B. DOI: 10.1016/j.apsb.2020.04.008

In the same publication, Chinese researchers also report that that crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites. The structural information of SARS-CoV-2 nucleocapsid protein remains unclear. A third group of researchers separately report on a molecular docking-based webserver they have developed, called D3Targets-2019-nCoV, for predicting drug targets and for multi-target and multi-site-based virtual screening of drugs against COVID-19. Both articles were originally published online in April. DOI: 10.1016/j.apsb.2020.04.009 and DOI: 10.1016/j.apsb.2020.04.006

After analyzing protein sequences for COVID-19 samples from all over the world, researchers at the University of Missouri identified three specific mutations—D614G, P323L and C241U—co-existing in every single case in the U.S. This could suggest why the virus seems to be so infectious in the country. (Their newest unpublished research indicates that resurgent COVID-19 viruses in European countries also have all three of the identified mutations in nearly all European cases.) A UM undergraduate student and middle school student in Columbia, Missouri used their computer programming skills to identify patterns in the sequences. Antiviral drugs currently being made to treat COVID-19 are developed based off the current model for the virus, but these mutations are co-evolving and causing the virus' structure to change so that those drugs may become less effective. DOI: 10.1007/s11481-020-09954-3

Researchers at Colorado State University report that neither domestic dogs nor cats developed clinical disease after being infected with SARS-CoV-2 and that infected dogs did not shed virus, whereas infected cats shed infectious virus orally and nasally for five days after infection and could infect other cats via direct contact. Cats re-exposed to the virus mounted an effective immune response and were not re-infected, suggesting that cats may be a useful model for vaccine development. Findings appeared in Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2013102117

By examining preexisting research for other conditions, researchers at the University of Cincinnati and multiple institutions in Germany report in the Journal of Biological Chemistry that they have found a potential treatment that could be applied to COVID-19. It’s a naturally occurring lipid in the human body called sphingosine known to be important in the lipid metabolism of all cells and the local immune defense in epithelial cells. Sphingosine has been shown in past studies to prevent and eliminate bacterial infections of the respiratory tract. Here, in experiments using cultured human cells with SARS-CoV-2 particles added, scientists show it binds into the cellular “lock,” the receptor ACE2, for the virus to prevent infection. Sphingosine could potentially be delivered as a nasal spray to prevent or treat infections, they say. DOI: 10.1074/jbc.RA120.015249

Scientists at Boston University's National Emerging Infectious Diseases Laboratories and the Center for Regenerative Medicine joined forces to develop a research model for understanding how SARS-CoV-2 impacts the lungs by engineering living, "breathing" human lung cells from stem cells for the task. According to their new findings, published in Cell Stem Cell, the trouble starts soon after the air sacs in the lungs are infected with virus, activating one of the body's biological pathways known as NFkB. Simultaneously, the virus also suppresses the lungs' ability to call in the help of the immune system to fight off the viral invaders. When the signal for help finally goes out days later, an army of immune cells swarms into lung tissue heavily laden with infected, dead, and dying cells and with unchecked levels of inflammation triggered by the early activation of NFkB. In attempting to destroy every infected cell in their path, the incoming immune cells add more fuel to the fire and can help send the lungs and other organs into total failure. The discovery of NFkB's role in this deadly cascade makes it a promising target for new therapeutics that could tamp down its activity early on after COVID-19 infection. Neither remdesivir nor camostat were found to completely control the inflammation unleashed by NFkB. DOI: 10.1016/j.stem.2020.09.013

Researchers from the University of California – Los Angeles and China have found that catalase, a naturally occurring enzyme, holds potential as a low-cost therapeutic drug to treat hyperinflammation that occurs due to COVID-19 and suppress the replication of coronavirus inside the body. A study detailing the research was published in Advanced Materials. Inside cells, the antioxidant enzyme kick starts the breakdown of hydrogen peroxide into water and oxygen. The team first demonstrated the enzyme's anti-inflammatory effects and its ability to regulate the production of cytokines, next showed that catalase can protect alveolar cells lining the human lungs from damage due to oxidation, and finally that catalase can repress the replication of SARSCoV2 in rhesus macaques without noticeable toxicity. DOI: 10.1002/adma.202004901

Research by infectious disease experts at the University of Rochester Medical Center suggests that past colds may provide some protection from COVID-19. In fact, immunity to COVID-19 is likely to last a long time—maybe even a lifetime. Their study, published in mBio, is the first to show that SARS-CoV-2 induces memory B cells to create antibodies to destroy the viral pathogen and remember it in the future, clearing infection before it starts. The study is also the first to report cross-reactivity of memory B cells, which could mean that anyone who has been infected by a common coronavirus—which is nearly everyone—may have some degree of pre-existing immunity to COVID-19. Findings are based on a comparison of blood samples from 26 people who were recovering from mild to moderate COVID-19 and 21 healthy donors whose samples were collected six to 10 years ago, specifically levels of memory B cells and antibodies that target specific parts of the spike protein (S2 subunits) common to all coronaviruses. DOI: 10.1128/mBio.01991-20  

The COVID-19 pandemic has created a flood of potentially substandard research amid the rush to publish, with a string of papers retracted or under a cloud and a surge in submissions to pre-print servers where fewer quality checks are made, a leading ethicist from Bond University (Australia) has warned in the Journal of Medical Ethics. As of May 7, 2020, 1,221 studies on COVID-19 were registered on the international clinical trial registry site, ClinicalTrials.gov, and as of July 31, 2020, 19 published articles and 14 preprints about COVID-19 have been retracted, withdrawn, or had serious doubts raised about the integrity of their data. Most of these papers came from Asia (57.5%), with over half coming from China (58%). The reason for known in three of the 33 cases that have come under scrutiny—unverifiable data (common across publications) and undisclosed conflict of interest. The authors also offer suggestions for remedying the situation. DOI: 10.1136/medethics-2020-106494

A study by researchers at Karolinska Institute (Sweden) and Max Planck Institute for Evolutionary Anthropology (Germany) that published in Nature shows that a Neandertal gene variant triples the risk of severe COVID-19. Their large international study linked a gene cluster on chromosome 3 to a higher risk of hospitalization and respiratory failure upon infection with the SARS-CoV-2 virus. The cluster is very similar to the corresponding DNA sequences of a roughly 50,000-year-old Neandertal from Croatia. The genetic risk variant is particularly common among people in South Asia (about half of the population carry the Neandertal risk variant). In Europe, one in six people carry the risk variant, while in Africa and East Asia it is almost non-existent. DOI: 10.1038/s41586-020-2818-3

 

Industry Updates  

In Sweden, SciLifeLab (one of the largest molecular biology research laboratories in Europe) and the Visualization Center (research and science center) are collaborating to set up an interactive exhibition about COVID-19. The project is designed to facilitate communication about complex data to the public in an attractive and educational fashion using interactive multi-touch display tables and 3D technology of Interspectral AB. The visualization combines four different types of research datasets on COVID-19: the SARS-CoV-2 virus architecture, the atomic structure of the spike protein, influenced human lungs, and global aspects of the pandemic. Press release.

Tufts University will lead a $100 million, five-year program to understand and address threats posed by zoonotic viral diseases that can "spill over" from animals to humans, such as SARS-CoV-2, in an effort to reduce risk of infection, amplification, and spread, the United States Agency for International Development has announced. Strategies to Prevent Spillover (aka STOP Spillover) will involve wildlife and human disease experts from both the university and organizations across the globe. These include the Africa One Health University Network; Broad Institute of the Massachusetts Institute of Technology and Harvard University; Humanitarian OpenStreetMap Team; International Centre for Diarrhoeal Disease Research, Bangladesh; Internews; JSI Research and Training Institute, Inc.; Southeast Asia One Health University Network; Tetra Tech ARD; the University of California, Los Angeles; the University of Glasgow Institute of Biodiversity, Animal Health, and Comparative Medicine; the Global Center for Health Security at the University of Nebraska Medical Center; and the University of Washington Institute for Risk Analysis and Risk Communication. Press release.

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