Sticky Webs, A Tiny Molecular Weapon, Obesity Paradox N/A: COVID-19 Updates
September 18, 2020 | New drug targets, reconstructing viral spread and lineage, monitoring mutations, reasons to focus on T-cell responses, DNA webs as culprits of tissue damage, a very tiny neutralizing agent, explaining paradoxical risk in people with obesity and diabetes, and the value of heparan. Plus, a new vaccine candidate heading to human trials, coronaviruses are being profiled, and a deep dive on how SARS-CoV-2 weakens the immune system.
Research Updates
Scientists from the University of Maryland School of Pharmacy report molecular-level investigations of SARS-CoV-2 and similar viruses SARS-CoV and MERS-CoV in the Journal of Chemical Physics, providing a possible pathway to new antiviral drugs to fight all three coronavirus diseases. They looked at papain-like protease (PLpro), a viral protein that plays a key role in the ability of the virus to replicate and in defeating the host's immune system, which is nearly identical in SARS-CoV-2 and SARS and slightly different in MERS-CoV. Investigators discovered small shifts in pH could change the shape of the enzyme via protonation, a process where hydrogen ions bind to certain amino acid units in the protein. They also found that the BL2 loop—the string of amino acid units at the PLpro binding site—can open or close in SARS viruses when a particular amino acid on the loop is either protonated or deprotonated. With the MERS virus, the loop is flexible even without such an amino acid. This feature suggests a potential drug could target the BL2 loop, causing it to close and tightly bind to a viral inhibitor. DOI: 10.1063/5.0020458
MicroRNA (miRNA) molecules are potentially capable of repressing the replication of human coronaviruses, including SARS-CoV-2, according to researchers at HSE University (Russia). As reported in PeerJ, the virus uses miRNA hsa-miR-21-3p to inhibit growth in the first stages of infection in order to delay the active immune response. Among all seven types of human coronaviruses, the team found four families of human miRNAs with binding sites, of which two—has-miR-21-3p and hsa-miR-421—are mutual for six of the coronaviruses. By analyzing available data on miRNA sequences in the lungs of mice infected with SARS-CoV, they discovered that infection leads to an eight-fold increase in the expression of the previously detected miRNA hsa-miR-21-3p. They plan to investigate the possibility of medicinal effect on the virus that targets the discovered miRNAs, e.g., if artificial introduction or elimination can prevent virus reproduction. DOI: 10.7717/peerj.9994
A new study combining evolutionary genomics from coronavirus samples with computer-simulated epidemics and detailed travel records has reconstructed the spread of coronavirus across the world in unprecedented detail. The results, published in Science, suggest an extended period of missed opportunity when intensive testing and contact tracing might have prevented SARS-CoV-2 from becoming established in North America and Europe. The paper also challenges suggestions that linked the earliest known cases of COVID-19 on each continent in January to outbreaks detected weeks later, and provides valuable insights that could inform public health response and help with anticipating and preventing future outbreaks of COVID-19 and other zoonotic diseases. Scientists from 13 research institutions in the U.S., Belgium, Canada and the U.K. participated in the effort, which involved analyzing results from viral genome sequencing efforts that began immediately after SARS-CoV-2 was identified. DOI: 10.1126/science.abc8169
Researchers at the University of Melbourne (Australia) have developed a software tool and library, dubbed COVID-3D, which harnesses genomic and protein information about SARS-CoV-2 to monitor mutations that make it difficult to develop COVID-19 vaccines and drugs. Several international universities and research institutions already using COVID-3D in vaccine and treatment development. As described in Nature Genetics, the Melbourne team analyzed the genome sequencing data of over 120,000 SARS-CoV-2 samples from infected people globally to identify mutations within each of the virus' proteins. They then tested and analyzed the mutations' effects on their protein structure using computer simulations. This data was used to calculate all the biological effects of every possible mutation within the genome. To help account for possible future mutations, mutations in the related coronaviruses SARS-CoV and Bat RaTG13 were also analyzed. DOI: 10.1038/s41588-020-0693-3
Although most vaccine developers are shooting for a robust antibody response to neutralize the virus and are focusing on the spike protein as the immunizing antigen, compelling evidence shows that the approach is problematic, a University of California – Berkeley researcher argues in a review article that published in Vaccine X. A better strategy is to take a lesson from one of the world's best vaccines, the 82-year-old yellow fever vaccine, which stimulates a long-lasting, protective T-cell response. Clinical research should look at the responses of T-cells during phase 2 trials and correlate them with who does well or not over the next several months to get a good sense of the laboratory features of vaccines that work. A technique developed in the author’s UC Berkeley lab can assess the lifespan of T-cells to tell within three or four months whether a specific vaccine will provide long-lasting cells and durable T-cell-mediated protection. DOI: 10.1016/j.jvacx.2020.100076
Sticky webs of DNA released from immune cells known as neutrophils may cause much of the tissue damage associated with severe COVID-19 infections, according to two new studies published in the Journal of Experimental Medicine. The research, conducted by independent groups in Belgium and Brazil, suggests that blocking the release of these DNA webs could be a new therapeutic target for the management of severe forms of COVID-19. An early indicator of severe COVID-19 is an increased number of circulating neutrophils, which can catch and kill invading microbes by unwinding their DNA and extruding it from the cell to form sticky webs—neutrophil extracellular traps (NETs)—which can also damage surrounding tissue and could be causing some of the lung pathology associated with severe COVID-19. One of the studies found large numbers of NETs dispersed throughout the lungs of patients who had succumbed to COVID-19, supporting the idea that targeting NETs may help alleviate thrombotic events, excessive tissue-damaging inflammation, fibrosis, and airway obstruction. The other study identified increased numbers of NETs in the lungs of severe COVID-19 patients as well as elevated NET formation in their blood plasma, and provided support for the use of inhibitors of NET synthesis or promoters of NET fragmentation as a strategy to ameliorate organ damage. DOIs:
10.1084/jem.2020101 and 10.1084/jem.20201129
University of Pittsburgh School of Medicine scientists have isolated the smallest biological molecule to date that completely and specifically neutralizes the SARS-CoV-2 virus. This antibody component, which is 10 times smaller than a full-sized antibody, has been used to construct a drug—known as Ab8—for potential use as a therapeutic and prophylactic against the novel coronavirus. As they report in Cell, Ab8 is highly effective in preventing and treating SARS-CoV-2 infection in mice and hamsters. Its tiny size not only increases its potential for diffusion in tissues to better neutralize the virus, but also makes it possible to administer the drug by alternative routes, including inhalation. Importantly, it does not bind to human cells and therefore is unlikely to have negative side effects in people. Ab8 was evaluated in conjunction with scientists from the University of North Carolina at Chapel Hill and University of Texas Medical Branch at Galveston, as well as the University of British Columbia and University of Saskatchewan. Abound Bio, a newly formed UPMC-backed company, has licensed Ab8 for worldwide development. It was found It was found by "fishing" in a pool of more than 100 billion potential candidates using the SARS-CoV-2 spike protein as bait. DOI: 10.1016/j.cell.2020.09.007
Researchers in Russia have discovered that FN3—a surface protein of the intestinal bacteria Bifidobacterium longum—can stop excessive or uncontrollable inflammation, as has been observed in COVID-19 patients. A fragment of this protein can be used as an anti-inflammatory medication when treating coronavirus and other diseases, they report in a study that published in Anaerobe. Their experiment showed that FN3 can bind TNF-α, one of the main cytokine storm factors. A preclinical trial of a new FN3-based anti-inflammatory medication is anticipated. DOI: 10.1016/j.anaerobe.2020.102247
In a study that published in the International Archives of Allergy and Immunology, scientists from Sechenov University (Russia) and the University of Bern (Switzerland) have concluded that the most advantageous strategy for COVID-19 vaccine development is to focus on inducing the production of high-affinity virus-neutralizing antibodies. These antibodies should block the interaction of SARS-CoV-2 with its cellular receptor—angiotensin-converting enzyme 2 (ACE2). Vaccines are also expected to polarize the T-cell response towards type 1 immunity and prevent the stimulation of cytokines that induce T-helper 2 immunity, they say. When researching potential vaccines for SARS-CoV-1, mice that received the whole spike protein (responsible for ACE2 binding) exhibited some eosinophilic complications in the lungs due to Th-2 polarization of the immune response. DOI: 10.1159/000509368
The epidemiological characteristics of SARS-CoV-2, its effects on field-based sciences and how working practices can be remodeled to overcome the challenges brought on by the virus are outlined in a commentary published in Nature Ecology & Evolution. The authors have wide-ranging expertise in archaeology, the allied geosciences and infectious disease dynamics and represent a diversity of views ranging from the Global North to the South, and from large countries to small island nations. Among their recommendations: creation and use of digital archives with community interpretation (goals that correspond well with an “open science” framework and make scientific research accessible to all); greater recognition of the value of technicians and greater investment in their training and recruitment; and increased financial support for method development. The paper also articulates how virtual training methods can be combined with safe, local and physically distanced training excavations. DOI: 10.1038/s41559-020-01317-8
A “molecular clock” analysis of SARS-CoV-2, looking at the rate that mutations accumulate in the virus and viral population, showed no widespread community distribution of the highly contagious coronavirus disease in Arizona until mid-February, according to initial findings reported by the Arizona COVID-19 Genomics Union (ACGU)—comprised of faculty at Northern Arizona University, the Translational Genomics Research Institute (TGen, an affiliate of City of Hope), University of Arizona (UA) and Arizona State University (ASU). The ACGU launched in early April to track the causative agent of COVID-19, how it evolves and how it spreads. It is sequencing the SARS-CoV-2 genomes in as many virus-positive patient samples in Arizona as possible, and the results are being applied to statewide efforts to test and track patients, as well as provide guidance for Arizona public policy makers. More than 80% of the SARS-CoV-2 genome sequences from Arizona COVID-19 cases descended from at least 11 separate lineages that were initially circulating widely in Europe, and by travel have since dominated the outbreak throughout the U.S. None of the observed transmission clusters are epidemiologically linked to the original travel-related case in the Arizona, suggesting successful early isolation and quarantine. TGen has so far sequenced SARS-CoV-2 genomes from almost 3,000 COVID-19 positive samples for the ACGU, and additional sequencing was performed at ASU and UA, from among the more than 200,000 positive cases in Arizona, making it one of the most robust such efforts in the nation. Results published in mBio. DOI: 10.1128/mBio.02107-20
The combined effects of the body's microbiota working together with COVID-19 in the lungs could explain the severity of the disease in people with obesity and diabetes, according to an article published in eLife. Paradoxically, obesity and diabetes tend to help patients recover better from lung conditions than people without those comorbidities. Researchers have found two mechanisms that may be making them more susceptible to COVID-19; one relates to the ACE2 receptor and the other an interaction between COVID-19 and pre-existing bacterial conditions. Some theorize that increased amounts of ACE2 in people with obesity or diabetes makes it easier for the virus to enter cells and increases the viral load; alternatively, increased shedding of ACE2 in people with obesity causes it to move to the lungs. People with obesity and diabetes are also thought to suffer from a body-wide dissemination of bacteria and the substances they produce, which in turn causes low-level continuous inflammation in different tissues. One potential culprit the authors point to is the lipopolysaccharides (LPS) that bacteria produce, which have been shown to cooperate with other coronaviruses to induce SARS in pigs. In humans, it is possible that these LPS molecules join forces with COVID-19 to trigger a chain of events that causes healthy tissue to transform into scarred tissue. They propose that a combined deficiency in ACE2 caused by COVID-19, together with obesity or diabetes, leads to impaired gut barrier function, allowing bacteria and their toxins to leak into the circulation. In the lungs, these bacteria and toxins work with the virus to cause more severe lung injury than either would do alone. DOI: 10.7554/eLife.61330
University of California San Diego School of Medicine researchers have discovered that SARS-CoV-2 can't grab onto ACE2 without a carbohydrate called heparan sulfate, which is also found on lung cell surfaces and acts as a co-receptor for viral entry. Their study, which published in Cell, introduces two new approaches that can reduce the ability of SARS-CoV-2 to infect human cells cultured in the lab by approximately 80%-90%. One is to remove heparan sulfate with enzymes. The other is to use heparin (a form of heparan sulfate already widely used to prevent and treat blood clots) as bait to lure and bind the coronavirus away from human cells. Early in the pandemic, the team discovered that the SARS-CoV-2 spike protein binds to heparin via the receptor binding domain and subsequently that enzymes that remove heparan sulfate from cell surfaces prevent SARS-CoV-2 from entering cells and that treating with heparin blocked infection. Researchers next need to test heparin and heparan sulfate inhibitors in animal models of SARS-CoV-2 infection. DOI: 10.1016/j.cell.2020.09.033
The latest study by researchers at La Jolla Institute for Immunology suggests the immune system does less harm than good for patients during the acute phase of COVID-19. Their work, published in Cell, confirms that a multi-layered, virus-specific immune response is important for controlling the virus during the acute phase of the infection and reducing COVID-19 disease severity, with the bulk of the evidence pointing to a much bigger role for T cells than antibodies. A weak or uncoordinated immune response, on the other hand, predicts a poor disease outcome. Vaccine candidates should therefore aim to elicit a broad immune response that includes antibodies, helper and killer T cells to ensure protective immunity. The authors say their observations could explain why older COVID-19 patients are much more vulnerable to the disease, since the reservoir of T cells that can be activated against a specific virus declines with age and the body's immune response becomes less coordinated. Conclusions were drawn from a detailed analysis of all three branches of the adaptive immune system in blood samples from 50 COVID-19 patients. DOI: 10.1016/j.cell.2020.09.038
Industry Updates
Vaxart, Inc. has announced that the FDA has completed its review of the company’s Investigational New Drug application for a phase 1 clinical trial evaluating its oral COVID-19 vaccine candidate and provided an update on its COVID-19 program. The room-temperature stable tablet is significantly easier and cheaper to store and distribute, as it does not require refrigerated cold chain required for injectable vaccines. The FDA-cleared open-label, dose-ranging study will be conducted in healthy adults ages 18 to 55 years old and its primary objective is to examine the safety and reactogenicity of two doses of the vaccine. In early August, the company also began a SARS-CoV-2 challenge study in hamsters to provide efficacy data and insights into the optimal dose regimen for its vaccine candidate; results are expected mid-October. Press release.
The University of Liverpool is leading a major new international project to improve understanding of severe coronavirus infection in humans and infirm vaccine development. Researchers will sequence and analyze samples from humans and animals to create profiles of various coronaviruses, including SARS-CoV-2. The FDA is supporting the initial three-year project with a $5.4 million award, bringing together collaborators from the University of Liverpool, Public Health England, the University of Bristol and the University of Oxford in the U.K.; A*STAR (Agency for Science, Technology and Research) in Singapore; and King Fahd Medical City in Saudi Arabia. The teams will use advanced transcriptomic/proteomic, immunological and computational techniques to analyze clinical specimens from people and model systems infected with coronaviruses that can cause severe disease in humans. The study will also examine newly developed technologies such as organ-on-chips to rapidly characterize coronaviruses/novel diseases and medical countermeasures. Press release.
Scientists at Sanford Burnham Prebys Medical Discovery Institute have released Coronascape—a customized version of the Metascape bioinformatics platform that removes big-data analysis hurdles for biologists—enabling scientists to interpret the growing body of big data related to COVID-19. More than 23,000 papers about COVID-19 have been published since January 2020 and continues to rise exponentially. Coronascape is designed to serve as a central clearinghouse for scientists to laser-focus their OMICs analysis and data-mining efforts to find effective drug targets, therapies and vaccines for COVID-19. It can take days if not weeks to generate actionable information by analyzing results from OMICs studies using sophisticated tools and highly trained computational scientists. Metascape launched in 2019 by scientists at Sanford Burnham Prebys, GNF and UC San Diego. Press release
Sanford Burnham Prebys Medical Discovery Institute has separately announced that its scientists have received a $3 million grant from the NIH to study how SARS-CoV-2 weakens the immune system—and identify drugs to help infected individuals recover. The goal is to learn how the coronavirus inactivates the “good” antiviral cytokine pathways needed to fight the virus and instead causes too much inflammation. Researchers will identify SARS-CoV-2 proteins that dysregulate cytokines and screen for therapeutically active drugs to restore balance to the immune system. They’ll also use animal models of coronavirus lung infection to investigate the signaling pathways that regulate antiviral cytokines. Two team members have also received research grants to screen for and validate existing drugs that can be repurposed to treat COVID-19. Press release.
