How SARS-CoV-2 Reaches the Brain, Bias in Human Gene Studies, Certain Foods Weaken Virus: COVID-19 Updates

December 4, 2020 I Genetic variations could affect severity, mouse model sheds light on loss of smell, virus mutations may not increase transmissibility, and immune mechanism that triggers cytokine storm. Plus: Chemical compounds in certain foods may weaken SARS-CoV-2, how the virus hijacks human lung cells, and 3D protein modeling shows animal susceptibility.

Research News

New 3D protein modeling shows why some animals may be more susceptible to COVID-19 than others. The study, published in PLOS Computational Biology, used computers to simulate how SARS-CoV-2 spike protein binds to an ACE2 receptor protein on the surface of different animal cells. They found that certain animals’ ACE2 “lock” fit the viral “key” better than others, making them more susceptible to infection with COVID-19. The simulations pinpointed certain structural features unique to the ACE2 receptors of these susceptible species, which include humans. Researchers hope that these findings can aid in development of therapeutic strategies to use artificial “locks” to trap the virus and prevent infection and improve models to monitor animal hosts from which a virus could potentially jump to humans, as previous research suggests spurred the current pandemic. DOI:10.1371/journal.pcbi.1008449

Mechanisms behind how SARS-CoV-2 hijacks human lung cells have been determined by Boston University School of Medicine researchers. The researchers examined lung alveolar cells from one to 24 hours after infection with the virus to understand what changes occur over this time period and what changes occur later. After comparing these changes to uninfected cells, they found that the cells infected with SARS-CoV-2 were drastically altered and observed abnormal changes in protein amounts and frequency of protein phosphorylation inside the cells. These abnormal changes allowed the virus to multiply and ultimately destroy the cells, resulting in widespread lung injury. The researchers then used these findings to identify potential treatments for COVID-19 and discovered 18 clinically approved drugs that can be repurposed to potentially block the proliferation of SARS-CoV-2 in lung cells. These findings are published in Molecular Cell. DOI:10.1016/j.molcel.2020.11.028

A repurposed mouse model, previously used to study SARS, sheds new light on loss of smell caused by COVID-19. The K18-hACE2 mice infected with a high dose of SARS-CoV-2 produced many of the same symptoms seen in people with severe COVID-19, including severe lung damage, vasculitis, blood clots, and death. They also displayed similar symptoms as people with mild disease, including the loss of smell. Researchers examined the cells in the nasal passage of these mice and their findings suggest that this may result from initial infection and damage to a type of cell that helps support the functions of neighboring sensory neurons that detect smell. They also found that mice treated with convalescent plasma from a patient who had recovered from the virus protected the mice from developing severe disease. This study is published in Nature. DOI:10.1038/s41586-020-2943-z

In a new study, published in the Journal of Experimental Medicine, researchers from Brazil pinpoint an immune mechanism that triggers cytokine storm seen in severe COVID-19. The research team demonstrated for the first time that in COVID-19 patients an immune mechanism, known as the inflammasome, plays an important role in the activation of the inflammatory process that can lead to organ damage and death. The authors suggest that their findings support the use of inflammasome activation as a marker for disease prognosis, identifying high-risk patients at an early stage, and as a potential therapeutic target in severe COVID-19. They report that there are drugs already approved for human use that are capable of inhibiting inflammasome activation and these drugs should be investigated in the context of SARS-CoV-2 infection. DOI:10.1084/jem.20201707

KU Leuven virologists have developed a vaccine candidate, tentatively named RegaVax, that protects against COVID-19 and yellow fever. To engineer the vaccine, the team inserted genetic code of the SARS-CoV-2 spikes into the genetic code of the yellow fever vaccine. The researchers first tested this vaccine candidate on hamsters and found that it provided protection from the virus after three weeks in all the hamsters from a single dose. They then tested the vaccine on monkeys and observed neutralizing antibodies just seven days after vaccination and all monkeys had high titers of neutralizing antibodies after fourteen days. Their results are published in Nature, and the team is preparing for clinical trials. DOI:10.1038/s41586-020-3035-9

A research team from Berlin has discovered that SARS-CoV-2 enters the brain via nerve cells in the olfactory mucosa. The study, published in Nature Neuroscience, examined tissue samples from 33 patients who died from severe COVID-19 and were able to produce the first-ever electron microscope images of intact coronavirus particles within the olfactory mucosa. Their findings suggest that the virus moves through nerve cells to reach the brain and is also transported through blood vessels, as evidence of SARS-CoV-2 was found in the walls of blood vessels in the brain. Additionally, they detected activated immune cells in the cerebral fluid as well as in the brain and olfactory mucosa. DOI:10.1038/s41593-020-00758-5

Chemical compounds in foods, such as green tea, muscadine grapes, and dark chocolate, may inhibit a key SARS-CoV-2 protease. North Carolina State University plant biologists used computer simulations and in vitro experiments to study chemical compounds from these foods and found that the compounds in green tea and muscadine grapes successfully inhibited the main protease (Mpro) in the SARS-CoV-2 virus in both computer simulations and lab studies. Cacao powder and dark chocolate chemical compounds reduced Mpro activity by roughly half in lab experiments. An author of this study, published in Frontiers of Plant Science, explains that inhibiting Mpro in the virus blocks replication and, in turn, kills SARS-CoV-2. DOI:10.3389/fpls.2020.601316

COVID-19 research should focus on mucosal immunity, say University of Buffalo researchers. Their paper, published in Frontiers in Immunology, recommends that studies are needed to determine the nature of mucosal secretory immunoglobulin A (SIgA) antibody responses over the course of infection, given that the initial sites of COVID-19 infection are in the mucous membranes of the nose and mouth and that early mucosal immune responses may successfully contain and eliminate the virus. The researchers add that a focus on mucosal immunity could make it possible to develop a nasal vaccine that would be easier to store and administer, while also potentially inducing immune responses where the virus makes its first contact. DOI:10.3389/fimmu.2020.611337

SARS-CoV-2 mutations do not appear to increase its transmissibility in human, according to new research led at the University College of London. The researchers analyzed virus genomes from over 46,000 people with COVID-19 and identified over 12,000 mutations up until the end of July 2020. They focused on 185 mutations that have occurred at least three times independently over the course of the pandemic and found no evidence of increased transmissibility after modeling the virus’s evolutionary tree. In particular, the D614G mutation, that has been widely reported as being a common mutation to make the virus more transmissible, was found to have no association with significantly increasing transmission. The researchers also found that the most common mutations seemed to have been induced by the human immune system, rather than being the result of the virus adapting to its novel human host. This study is published in Nature Communications. DOI:10.1038/s41467-020-19818-2

New research led at Beth Israel Deaconess Medical Center reveals how genetic variations may affect the severity of COVID-19 disease. Growing research has linked two regions of the human genome to COVID-19 outcomes, and the team sought out to understand which proteins in these genome sections play an important role in COVID-19 disease. Using an expansive library of all proteins and metabolites associated with various regions of the human genome, the researchers determined that the protein most highly expressed in one genomic “hot spot” is also a co-receptor for SARS-CoV-2 and may be a target for therapeutic interventions. They also explored a second region that was linked to a poorly understood protein that may play a role in attracting lymphocytes to the site of infection, but they note that this finding warrants further research. Early analyses from their work also suggests that these genetic variants and proteins can vary across races. Their findings are published in the New England Journal of Medicine. DOI:10.1056/NEJMc2025747

University of Warwick researchers have designed a computational model of a human lung cell that demonstrates how SARS-CoV-2 uses its host to survive and predicts cellular drug targets against the virus. The researchers have captured the stoichiometric amino and nucleic acid requirements of SARS-CoV-2 using this model and determined that only a few metabolic perturbations are able to selectively inhibit virus reproduction. The team also noted that some of the catalyzing enzymes of such reactions have demonstrated interactions with existing drugs and suggest that their findings highlight the possibility of targeting host metabolism for inhibition of viral reproduction in human cells, specifically human lung cells. This study is published in Life Science Alliance. DOI:10.26508/lsa.202000869

Many human genes are not being included in COVID-19 research due to historical bias, according to new research from Northwestern University. The researchers explain that current experimentation focuses on human genes that have already been heavily investigated and tends to build upon existing knowledge and research tools, due to ease of experimentation rather than their ultimate relevance. This new research builds upon a previous study that found 30% of all genes have never been studied and less than 20% of genes are the subject of more than 90% of published papers. These findings are published in eLife. DOI:10.7554/eLife.61981

In a new study, published in the New Journal of Chemistry, researchers from the Politecnico di Milano have identified a mechanism that may block SARS-CoV-2 replication. The identified compound, called EBSELEN, was found to be a potent inhibitor of Mpro, which is a protein that plays an important role in the replication and transcription of the virus. The research team also identified that the selenium atom of EBSELEN strongly interacts with some groups typically present in proteins via the chalcogen bond and this binding may contribute to the inhibition of the virus’ replication. Additionally, selenium plays an important role in establishing interactions that favor binding of EBSELEN to SARS-CoV-2 and to other 0pathogenic retroviruses in humans. DOI:10.1039/D0NJ04647G

Industry News

Owkin has announced a collaboration with the Institut Pasteur to focus on developing a new machine learning model capable of identifying COVID-19, along with other coronaviruses, epitopes with high immunogenic potential that could be used for future coronavirus vaccines. Owkin is a startup company that deploys artificial intelligence and Federated Learning technologies to support medical research, accelerate drug development, and enable scientific discoveries. Institut Pasteur is a private, non-profit foundation whose mission is to help prevent and treat diseases, specifically infectious diseases, through research, teaching, and public health initiatives. Press Release

The Bill & Melinda Gates Foundation has awarded Texas Biomedical Research Institute (Texas Biomed) $1 million to fund testing of human monoclonal antibodies (MAbs) for the treatment of COVID-19. Texas Biomed researchers will evaluate the protective efficacy of the MAbs in small rodent models on behalf of the Coronavirus Immunotherapy Consortium (CoVIC). They will receive MAbs from laboratories around the globe and test different concentrations and possible combinations of multiple MAbs to determine what provides lasting protection in the rodent models. Press Release