Beetle Viruses, Nitrate Supplements, Missing Sense of Smell: COVID-19 Updates
August 21, 2020 | How a beetle virus is informing SARS-CoV-2 research, plus nitrate supplementation for aid breathing, new small molecules active against the virus, and a theory for why COVID-19 patients lose their sense of smell. Plus, $9.8 million from DOD for vaccine research and virus-like particles for vaccine development.
Literature Updates
Researchers at the University of Otago (New Zealand) recently led a study showing that a virus serving as a biocontrol agent against the coconut rhinoceros beetle uses a "decoy" strategy to evade the immune system. They are now using the discovery to learn more about SARS-CoV-2. Viruses that replicate and assemble inside the nucleus have evolved special approaches to modify the nuclear landscape to their advantage, they explain. The research team used electron microscopy to learn the Oryctes rhinoceros nudivirus acquires a membrane inside the nucleus of the infected cell, and it gets fully equipped to infect new cells at this precise location. This is in contrast with other enveloped viruses, including coronavirus, which derive their membranes from other cellular compartments. The implication is that many of the viruses released by the infected cells will be enclosed in a cellular membrane while travelling inside the infected organism—meaning, they will be missed by the immune system and use this membrane decoy to penetrate any other type of cells without the need of a virus-specific receptor. Their research published in mBio. DOI: 10.1128/mBio.01333-20
Dietary nitrate supplementation could aid breathing and lung clearance in the elderly, and potentially help older COVID-19 patients get weaned from mechanical ventilation, suggests a study done in old mice by researchers at the University of Florida that published in The Journal of Physiology. Nitrate was shown to improve functioning of the diaphragm, the primary inspiratory muscle used for breathing and coughing. Researchers made their measurements during maximal activation, so the effects observed seem to be caused by an improvement in the function of contractile proteins rather than calcium handling. The benefits to people may not as pronounced as was observed in mice, they note, since the human diaphragm consists of 25-50% fast muscle cells versus 90% in the rodents. DOI: 10.1113/JP280027
A team of researchers at the Pritzker School of Molecular Engineering at the University of Chicago used state-of-the-art computer simulations to show how a preexisting drug Ebselen—used to treat multiple diseases, including bipolar disorders and hearing loss—binds to the main protease (Mpro) of SARS-CoV-2. Ebselen was found to bind at the catalytic site of the enzyme as well as to a distant site, which interferes with the enzyme's catalytic function. The newly discovered vulnerability in the virus could be use useful in developing new therapeutic strategies against COVID-19. Findings appeared in Science Advances. DOI: 10.1126/sciadv.abd0345
Scientists at the University of Hong Kong have identified a small molecule—N-(p-Amylcinnamoyl) anthranilic acid (ACA)—which inhibits multiple different viruses, including SARS-CoV-2, in tissue culture and in mice by targeting the same TGF-β signaling pathway. The finding, appearing in Science Advances, suggests a possible target for broad-spectrum antiviral drugs. The team found that ACA achieved its inhibitory effect by blocking the interaction of AP2M1, a subunit of the AP2 adaptor complex that is known to interact with the TGF-β pathway, with an amino acid sequence present in many viral proteins. Blocking this host-virus protein interaction interfered with proper subcellular localization of virus components, thereby inhibiting a productive infection. DOI: 10.1126/sciadv.aba7910
The reason the COVID-19 virus is deadly, while many other coronaviruses are innocuous, is because SARS-CoV-2 acts as a microRNA “sponge,” report a team of University of Alabama at Birmingham and Polish researchers in a study that published in the American Journal of Physiology-Lung Cellular and Molecular Physiology. This action modulates host microRNA (miRNA) levels in ways that aid viral replication and stymies the host immune response. Their hypothesis: miRNAs are only about 0.01% of total human cell and tissue RNA, so if the COVID-19 virus has binding sites for specific miRNAs and these are different than the binding sites for miRNAs found on coronaviruses that cause colds, the more pathogenic COVID-19 virus may selectively sponge up certain miRNAs to dysregulate the cell in ways that make it a dangerous human coronavirus. Such sponge activity has previously been shown for the Epstein-Barr virus as well as the herpes and hepatitis C viruses. Researchers used computer-aided bioinformatic analysis to find potential miRNA target sites for 896 mature human miRNA sequences on seven different coronavirus genomes. They found that the number of target sites was elevated in the pathogenic viruses compared to the non-pathogenic strains, and they also attracted different sets of miRNAs. A majority of the 28 miRNAs unique to the COVID-19 virus were found to be well expressed in bronchial epithelial cells, and their dysregulation has been reported in human lung pathologies. DOI: 10.1152/ajplung.00252.2020
Researchers in Germany have structurally analyzed the spike (S) protein of SARS-CoV-2 in situ and found that, relative to recombinant S, it is more heavily glycosylated and occurs mostly in the closed prefusion conformation. They showed that the stalk domain of S contains three hinges, giving the head unexpected orientational freedom. The hinges may allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat. Findings, published in Science, contribute to understanding of SARS-CoV-2 infection and the development of safe vaccines. DOI: 10.1126/science.abd5223
Scientists at La Jolla Institute for Immunology have tracked down the rare stem cells that generate neutrophils in human bone marrow, giving researchers a potential path for intervening in diseases where neutrophil development goes awry. Immature neutrophils have been found to be elevated in both the blood and lungs of severe COVID-19 patients, they note. The new research, published in Immunity, revealed a progenitor cell type that exists even earlier in human neutrophil development than previously thought. The means was a tool called “cytometry by time-of-flight" to distinguish these rare cells from other types of immune progenitor cells, making it possible to identify more specific protein markers on the early progenitor cell surface. Neutrophil development can now to tracked from day one. Researchers theorize that the threat of SARS-CoV-2 prompts the body to churn out neutrophils too quickly, forcing immature cells off the track to maturity. DOI: 10.1016/j.immuni.2020.07.017
A novel receptor protein that binds to the SARS-CoV-2 virus and prevents it from entering cells may hold promise for treating COVID-19 and other coronavirus-related diseases, according to research published online in Science. Researchers at the University of Illinois, together with the U.S. Army Medical Research Institute of Infectious Diseases, designed and tested the decoy protein that can bind to the virus before it can latch onto angiotensin-converting enzyme 2 (ACE2) at the cell surface and invade the cell. After analyzing more than 2,000 ACE2 mutations, Illinois scientists discovered three that together made a receptor that bound to the virus more strongly and made it a more "attractive" target for the virus. USAMRIID scientists then tested the receptor in cells using live SARS-CoV-2. The decoy receptor was found to have neutralizing activity against SARS-CoV-2 on par with the best neutralizing antibodies identified to date. It was also shown to neutralize SARS-CoV-1, which uses the same cellular receptor. DOI: 10.1126/science.abc0870
Researchers at Johns Hopkins University School of Medicine studying tissue removed from patients’ nose during endoscopic surgery believe they may have discovered the reason why so many people with COVID-19 lose their sense of smell, even when they have no other symptoms—extremely high levels of angiotensin converting enzyme II (ACE-2) only in the area of the nose responsible for smelling. Their findings, published in the European Respiratory Journal, offer clues as to why COVID-19 is so infectious and suggest that targeting this part of the body could potentially offer more effective treatments. In addition to surgically removed tissue samples from the olfactory epithelium of 23 patients, the research team also studied biopsies from the trachea of seven patients; none of the patients had been diagnosed COVID-19. The levels of ACE2 in olfactory epithelium cells was between 200 and 700 times higher than other tissue in the nose and trachea, and similarly high levels were found in all the samples regardless of whether the patient had been treated for chronic rhinosinusitis or another condition. ACE2 was not detected on olfactory neurons, the nerve cells that pass information about smells to the brain. DOI: 10.1183/13993003.01948-2020
Genes that play an important role in allowing SARS-CoV-2 to invade heart cells become more active with age, according to research published in the Journal of Molecular and Cellular Cardiology. The findings could help explain why age is major risk factor for dying from COVID-19, with people over 70 years at greatest risk, and why the disease can cause heart complications in severe cases, including heart failure and inflammation of the heart. The team included researchers from the University of Cambridge (U.K.), Maastricht University (Netherlands), KU Leuven (Belgium) and Karolinska Institute (Sweden). They examined cardiomyocytes to see how susceptible they were to infection by the coronavirus, since damage to these cells can affect the ability of the heart muscles to perform, leading to heart failure. Comparing the cardiomyocytes from five young (ages 19 to 25) males to that of five older (ages 63 to 78) males, they found the genes that give the body instructions to make these proteins were all significantly more active in the cardiomyocytes from the older males. This suggests the likelihood of an increase in the corresponding proteins in aged cardiomyocytes. Some of the proteins encoded by the genes can be inhibited by existing medicines, such as the anti-inflammatory drug camostat that inhibits TMPRSS2 and has been shown to block SARS-CoV-2 entry in cells grown in the laboratory. DOI: 10.1016/j.yjmcc.2020.08.009
High levels of some cytokines seen in COVID-19 patients, as part of a cytokine storm, may prevent the development of long-term immunity to SARS-CoV-2, according to a study destined for publication in Cell. In patients with both mild as well as severe disease, antibodies lacked a key structural feature that is a hallmark of the highest quality antibodies in a normal immune response, they say. Examining the spleens and lymph nodes of deceased COVID-19 patients, researchers found a lack of germinal centers, an essential part of a durable immune response where antibody-producing B cells mature to become long-lived memory cells. To form germinal centers, B cells depend on key support from a specialized type of helper T cells that do not develop in COVID-19 patients. The study found no germinal centers in acutely ill patients. The body is still mounting an immune response, but the fact that it is not coming from a germinal center could have major implications for development of herd immunity. While antibodies may protect people for a relatively short time, a single person who recovers from the disease could get infected again, perhaps six months later, or even multiple times. A vaccine-induced immune response, they note, would likely include the development of a germinal center. DOI: 10.1016/j.cell.2020.08.025
Industry Updates
Adaptive Phage Therapeutics (APT) has announced a $9.8 million award from the Department of Defense for research development of multiple high-priority, bacteriophage-based display vaccine candidates against the novel coronavirus. The effort will advance and evaluate vaccine candidates in phase 1 clinical trials. APT is the only biotechnology company with a phage-based COVID-19 vaccine program projected to enter clinical trials in 2020. Phage-based vaccines offer significant potential benefits by establishing a platform approach with the ability to quickly adjust the vaccine in response to mutations in the coronavirus. They are additionally “self-adjuvanted,” meaning they automatically activate and boost immune response with the ability to display multiple antigens. APT is a clinical-stage company founded to provide an effective therapeutic response to the global rise of multi-drug resistant pathogenic bacteria. Press release.
Scientists from the CUNY School of Medicine at The City College of New York (CCNY) and TechnoVax, Inc. report that they have generated and characterized SARS-CoV-2 virus-like particles (VLPs) that are structural mimics of the native virus in size, morphology and surface composition but devoid of viral, infection causing, genetic material. These features of the VLP platform make it an ideal candidate for COVID-19 vaccine development, they say. The technology has a proven track record as evidenced by the success of vaccines directed against human papillomavirus virus and hepatitis B virus. For COVID-19, the VLPs were assembled in a suspension culture of mammalian cells from both the coronavirus structural elements as well as uniquely modified surface spike molecules specifically designed to ensure stability, abundance, and the immunogenic properties known to be essential for creation of a highly effective vaccine. CCNY and TechnoVax are entertaining inquiries from potential partners to collaborate in further developing this alternative vaccine solution. Press release.