More ‘Omics for SARS-CoV-2, Insights into the Spike Protein, Crowdsourcing Questions: COVID-19 Updates
September 25, 2020 | A Canadian team shares a new mechanism of action for remdesivir, data science groups have computed consensomes (gene expression in the virus) and interactomes (potential molecular mechanisms of pathogenesis) and cryoEM images the spike protein. Plus, NIH funding for new vaccines and the Reliable Response Data Discovery consortium takes COVID-19 patient data questions.
Research Updates
Researchers at the University of Alberta have discovered a novel, second mechanism of action by the antiviral drug remdesivir against SARS-CoV-2, according to findings published today in the Journal of Biological Chemistry. The research team previously demonstrated how remdesivir inhibits the COVID-19 virus’s polymerase or replication machinery in a test tube; the newly identified mechanism of action stops or heavily delays replication of the virus, which in turn reduces propagation and spread. DOI: 10.1074/jbc.AC120.015720
University of Alabama at Birmingham researchers have built an interactome that includes the lung-epithelial cell host interactome integrated with a SARS-CoV-2 interactome. Applying network biology analysis tools to this human/SARS-CoV-2 interactome has revealed potential molecular mechanisms of pathogenesis for SARS-CoV-2, the authors write in iScience. They identified 33 high-value SARS-CoV-2 therapeutic targets, which are possibly involved in viral entry, proliferation and survival to establish infection and facilitate disease progression. These molecular insights may foster effective therapies, using combinations of existing drugs, for patients with COVID-19. DOI: 10.1016/j.isci.2020.101526.
Two UC San Diego Health groups have published research suggesting that statins—widely used cholesterol-lowering medications—are associated with reduced risk of developing severe COVID-19 disease, as well as faster recovery times. The first reported the correlation; a second team found that removing cholesterol from cell membranes prevents the coronavirus from getting in. The clinical study was published in the American Journal of Cardiology showing a connection. DOI: 10.1016/j.amjcard.2020.09.012 The mechanistic study was published in The EMBO Journal. DOI: 10.15252/embj.2020106057
Baylor College of Medicine and the University of California San Diego researchers used publicly archived transcriptomic datasets to compute consensus regulatory signatures, or consensomes, that rank human genes based on their rates of differential expression in MERS-CoV (MERS), SARS-CoV-1 (SARS1) and SARS-CoV-2 (SARS2)-infected cells. Validating the CoV consensomes, the team shows that high confidence transcriptional targets (HCTs) of MERS, SARS1 and SARS2 infection intersect with HCTs of signaling pathway nodes with known roles in CoV infection. The researchers hypothesize that SARS2 infection efficiently represses E2F family HCTs encoding key drivers of DNA replication and the cell cycle; that progesterone receptor signaling antagonizes SARS2-induced inflammatory signaling in the airway epithelium; and that SARS2 HCTs are enriched for genes involved in epithelial to mesenchymal transition. They published their work in Scientific Data. DOI: 10.1038/s41597-020-00628-6
Researchers at the University of Bristol used cryo-EM to analyze the SARS-CoV-2 spike protein at near atomic resolution. Enabled by Oracle high-performance cloud computing, a 3D structure of SARS CoV-2 Spike protein was generated allowing the researchers to peer deep inside the Spike identifying its molecular composition. Unexpectedly, the research team's analysis revealed the presence of a small molecule, linoleic acid (LA), buried in a tailor-made pocket within the spike protein. LA is a free fatty acid, which is indispensable for many cellular functions. The human body cannot produce LA. Instead, the body absorbs this essential molecule through diet. Intriguingly, LA plays a vital role in inflammation and immune modulation, which are both key elements of COVID-19 disease progression. LA is also needed to maintain cell membranes in the lungs so that we can breathe properly. DOI: 10.1126/science.abd3255
Boston University researchers present an in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2, using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture. They find a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-kB signaling and loss of the mature alveolar program. According to the researchers, the inflammatory signals initiated by the infected pneumocytes attract an army of immune cells into lung tissue laden with infected and already dead and dying cells. They published their work in Cell Stem Cell. DOI: 10.1016/j.stem.2020.09.013
Researchers from the University of Georgia modeled herd immunity in Great Britain and published their findings in PNAS. By simulating SARS-CoV-2 spread in the United Kingdom and attempting to model herd immunity, the researchers found that success without overwhelming hospital capacity leaves little room for error. Intervention levels must be carefully manipulated in an adaptive manner for an extended period, despite acute sensitivity to poorly quantified epidemiological factors, they write. Such fine-tuning of social distancing renders this strategy impractical. DOI: 10.1073/pnas.2008087117
Spanish researchers are exploring how 4-Phenylbutiric acid (4-PBA) treatment modulates the inflammatory response produced in severe cases of COVID-19. The project has been financed by the COVID-19 Fund of the Government of Andalusia, with an initial endowment of EUR 90,000 and the possibility of a three-year renewal. First results have already been published in the scientific journal Cytokine and Growth Factors Review. DOI: 10.1016/j.cytogfr.2020.06.011
Researchers at Princeton used several epidemiological models to study the possible future of SARS-CoV-2 infections. They found that the impact of natural and vaccine-induced immunity will be key factors in shaping the future trajectory of the pandemic. In particular, a vaccine capable of eliciting a strong immune response could substantially reduce the future burden of infection. The work is published in Science and builds on previous research also published in Science that reported that local variations in climate are not likely to dominate the first wave of the COVID-19 pandemic and included many of the same authors, who are all affiliated with PEI's Climate Change and Infectious Disease initiative. DOI: 10.1126/science.abd7343
Similar to many other viral fusion proteins, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Researchers from the University of California, San Diego, built a full-length model of the glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans and on the protein structure and dynamics. We reveal an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike’s receptor binding domain (RBD), which is responsible for ACE2 recognition. The work is published in ACS Central Science. DOI: 10.1021/acscentsci.0c01056
In mBio, German researchers analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells. The new data suggest that cytotoxic T cells play a key role in control of early infections, but the authors cautioned that it's too soon to know if that connection can be harnessed to design an effective immunotherapy that uses these cells. DOI: 10.1128/mBio.02243-20.
Scientists from the National Center for Advancing Translational Sciences (NCATS) and Naval Research Laboratory (NRL) in Washington, D.C., have developed a fluorescent nanoparticle probe that uses the spike protein on the surface of SARS-CoV-2 to bind to cells and trigger the process that pulls the virus into the cell. The probe could be used in tests to rapidly gauge the ability of biologics, drugs and compounds to block the actual virus from infecting human cells. The work was published in ACS Nano. DOI: 10.1021/acsnano.0c05975
Researchers in Australia have developed a mathematical framework for determining second surge behavior of COVID-19 cases in the United States. Within this framework, a flexible algorithmic approach selects a set of turning points for each state, computes distances between them, and determines whether each state is in (or over) a first or second surge. Then, appropriate distances between normalized time series are used to further analyze the relationships between case trajectories on a month-by-month basis. The algorithm shows that 31 states are experiencing second surges, while four of the 10 largest states are still in their first surge, with case counts that have never decreased. This analysis can aid in highlighting the most and least successful state responses to COVID-19. Their work was published in Chaos. DOI: 10.1063/5.0024204
In a study of 65 COVID-19 patients younger than 24 and 60 older patients, researchers detected key differences in immune response that may contribute to understanding why children usually have milder disease than adults. The study was published in Science Translational Medicine and was conducted by scientists at Albert Einstein College of Medicine, Children's Hospital at Montefiore (CHAM), and Yale University. Children with COVID-19 fared significantly better than adults. Thirty seven percent of adults required mechanical ventilation compared with only 8% of the pediatric patients. In addition, 28% of adults died in the hospital compared with 3% of the pediatric patients. The researchers posit that children with COVID-19 do better than adults because their stronger innate immunity protects them against SARS-CoV-2. DOI: 10.1126/scitranslmed.abd5487
A team of researchers at Cleveland Clinic analyzed more than 13,000 patients tested for COVID-19 at Cleveland Clinic between early March and mid-April of this year and compared those who had received unadjuvanted influenza vaccines in the fall or winter of 2019 (4,138 patients) against those who did not received the vaccine (9,082 patients). Publishing in the Journal of Clinical and Translational Science, they found that the 2019 influenza vaccination was not associated with increased COVID-19 incidence or disease severity, including risk for hospitalization, admission to the intensive care unit or mortality. They recommend that we should proceed as usual with our vaccination strategy for global influenza this flu season. DOI: 10.1017/cts.2020.543
In Science Advances, Japanese researchers report a high-speed in vitro selection of multiple high-affinity antibody-like proteins against various targets including the SARS-CoV-2 spike protein. The sequences of monobodies against the SARS-CoV-2 spike protein were successfully procured within only four days. Furthermore, the obtained monobody efficiently captured SARS-CoV-2 particles from the nasal swab samples of patients and exhibited a high neutralizing activity against SARS-CoV-2 infection. The high-speed in vitro selection of antibody-like proteins would be useful for the rapid development of a detection method and a neutralizing protein against a virus responsible for an ongoing, and possibly a future, pandemic. DOI: 10.1126/sciadv.abd3916
The spike protein on the surface of the SARS-CoV-2 coronavirus can adopt at least ten distinct structural states when in contact with the human virus receptor ACE2, according to a Francis Crick Institute study published in Nature. A SARS-CoV-2 infection begins when a spike protein binds with ACE2 cell surface receptors and, at later stages, catalyzes the release of the virus genome into the cell. The team used cryoEM to view the binding of ACE2 to the virus spike protein. They observed that the spike protein exists as a mixture of closed and open structures., Following ACE2 binding at a single open site, the spike protein becomes more open, leading to a series of favorable conformational changes, priming it for additional binding. Once the spike is bound to ACE2 at all three of its binding sites, its central core becomes exposed, which may help the virus to fuse to the cell membrane, permitting infection. DOI: 10.1038/s41586-020-2772-0
Data scientists used dimensionality reduction and topic modeling to analyze the deluge of COVID-19 related publications. By reading the full text of the publications, they found that basic lab-based studies on the microbiology of the virus, including research on its pathogenesis and mechanisms of viral transmission, are lacking. Their analysis appears in Patterns. They also note that research has changed over time, with an acceleration in studies examining public health responses, clinical issues related to the virus, the societal impact of the outbreak, and how the disease spreads across populations, while reporting on the status of the outbreak has begun to plateau. DOI: 10.1016/j.patter.2020.100123
Industry Updates
A team of scientists at Colorado State University was awarded a base contract worth $3.1 million from the National Institutes of Health to continue development of a coronavirus vaccine candidate known as SolaVAX. The funding includes an additional $15.5 million over five years if all options are implemented. The additional funding will support pre-clinical research and a move to Phase I human clinical trials to test the safety and immune response of the vaccine. SolaVAX repurposes a commercial platform that is currently used to inactivate pathogens in blood transfusions. The strategy uses UV light and riboflavin to create an inactivated virus, which stimulates a person's immune system to fight the virus. The research team aims to demonstrate the effectiveness of the SolaVAX process to inactivate SARS-CoV-2, which causes COVID-19, to be used in a vaccine against the disease. Press release.
An international group of researchers are investigating how and why the strategies implemented by countries to deal with the current pandemic succeeded or failed. The study is supported by FAPESP and coordinated by researchers at Getúlio Vargas Foundation (FGV) in São Paulo, Brazil, and the University of Michigan in the United States. A book is planned with comparative analyses of countries and regions. The project also calls for primary data collection during the pandemic, and for the creation of a repository as a basis for future studies, with news stories and data on political leaders, government communication, and public policies. Press release.
A new research consortium, Reliable Response Data Discovery (R2D2), invites clinicians, researchers, patients and the general public to submit questions that could be answered by COVID-19 patient record data from more than 200 participating hospitals. Questions are submitted and answers are provided via a new web portal: COVID19questions.org. Unlike other patient databases and registries, the R2D2 COVID-19 Questions site allows health systems to maintain control of their own data rather than pool it in a central repository. No patient-level data are ever transmitted outside of each health system, only data aggregates, and the privacy of individuals and institutions is preserved. Through advanced computational methods, complex analyses involving multiple factors can be performed. Since the system queries all patient records, not just those with COVID-19, users can ask questions about how patients with COVID-19 compare to other patients. Press release.
Integral Molecular has been awarded $521,723 from the Commonwealth of Pennsylvania to leverage its technologies in the global fight against COVID-19. The grant will enable Integral Molecular and its partners to develop therapeutics and vaccines with broad specificity against SARS-CoV-2 variants using four of its technology platforms: MPS Antibody Discovery platform to generate broadly reactive antibodies against SARS-CoV-2 and other coronaviruses; SARS-CoV-2 Reporter Virus Particles (RVPs) have been adopted by vaccine companies to safely test for neutralizing immune responses in patients and vaccines; Membrane Protein Array (MPA) is being used to rapidly screen the specificity of SARS-CoV-2 antibodies to advance the most promising candidates; and Shotgun Mutagenesis Epitope Mapping is being used to optimize vaccine and antibody design, so that resulting therapeutics and vaccines recognize emerging SARS-CoV-2 variants. Press release.
