Oral Antiviral Blocks Transmission, Multi-Organ Failure Mechanisms, Molecular Target for Lung Fibrosis: COVID-19 Updates

December 11, 2020 I IgA antibodies dominate early neutralizing response, specific proteins in animals increase vulnerability, understanding the roles of antibodies and T cells, and Molnupiravir could block SARS-CoV-2 transmission. Plus: New biomedical data sharing platform, disrupting cholesterol processes may combat COVID-19, and a new project aims to understand formation of coronaviruses.

Research News

New research has identified critical molecular processes in human cells that SARS-CoV-2 and other coronaviruses use to survive and multiply. This study, published in Cell, infected human cells with SARS-CoV-2 or two other coronaviruses that cause common colds and studied how different mutations to those human cells made them less vulnerable to the viruses. They determined that human cells engineered to lack genes that control cholesterol and phosphatidylinositol phosphate (PIP) were protected from infection of all three coronaviruses. Not surprisingly, human cells with a mutation to the ACE2 gene were not infected by SARS-CoV-2. The researchers suggest that targeting cholesterol or PIP could be a new strategy to combat not only COVID-19, but a broad range of coronaviruses. DOI:10.1016/j.cell.2020.12.004

In a new study, published in JCI Insight, researchers from the University of California, Los Angeles (UCLA) created a mouse model that demonstrates how COVID-19 damages multiple organs, other than the lungs. The UCLA researchers engineered mice to have the human version of ACE2 in the heart and other organs and infected half of those mice by injected SARS-CoV-2 into their bloodstreams. They found that within seven days, all the mice with COVID-19 had lost, on average, 20% of their body weight. In comparison, the other half of the uninfected mice did not lose any significant amount of weight. They determined that the virus had shut down energy production in cells of the heart, kidneys, spleen and other organs. The team also noted some long-lasting changes to the structure of DNA in these mice, which could explain why some people experience persistent COVID-19 symptoms, according to the researchers. DOI:10.1172/jci.insight.145027

IgA antibodies dominate the early neutralizing antibody response to SARS-CoV-2, finds a new study published in Science Translational Medicine. Researchers studied samples from over 150 COVID-19 patients with mild to severe symptoms and found that IgA concentrations were higher than IgG and IgM concentrations in the first 3 to 4 weeks after symptom onset and then waned, however, IgA antibodies persisted in saliva for several more weeks. In a separate study, the researchers cloned antibodies taken from recovered COVID-19 patients and discovered that the dimeric form of IgA was fifteen times better at neutralizing the SARS-CoV-2 virus then the monomeric form. Based on these findings, they suggest vaccine development that induces an IgA response and IgA-based tests to detect infection at early stages. DOI:10.1126/scitranslmed.abd2223

A promising new molecular target to treat pulmonary fibrosis, including cases caused by SARS-CoV-2 infection, has been identified in a new study published in Science Advances. Researchers studied lung tissue samples from patients with different types of pulmonary fibrosis, including COVID-19 cases, and mouse models of pulmonary fibrosis triggered by the administration of bleomycin. They found that all cases were characterized by the overexpression of MBD2 and this activity localized in areas occupied by macrophages. To study this further, they depleted this Mbd2 gene in macrophages in some of the mice and administered liposomes loaded with Mbd2 silencer RNA into tracheas of other mice, and they found that both groups of mice were protected against lung fibrosis. The researchers hypothesize that inhibiting MBD2 could be an effective way to treat this lung disease. DOI:10.1126/sciadv.abb6075

Beth Israel Deaconcess Medical Center (BIDMC) researchers have determined the roles of antibodies and T cells in protection against COVID-19. Building on prior research that showed previous SARS-CoV-2 infection protects rhesus monkeys from reinfection, the researchers collected and purified antibodies from monkeys that had recovered from the virus and administered these antibodies at various concentrations to uninfected monkeys. They found that those monkeys that received higher concentrations of the antibodies were better protected against COVID-19, although those receiving a lower dose had some protection. They then evaluated the role of T cells and found that by removing these immune cells in recovered monkeys, the animals were left more vulnerable to reinfection of the virus. The study, published in Nature, concludes that antibodies alone can protect against SARS-CoV-2 at relatively low levels, but T cells are beneficial if antibody levels are not sufficient. DOI:10.1038/s41586-020-03041-6

The oral antiviral drug, Molnupiravir (MK-4482/EIDD-2801), could potentially block SARS-CoV-2 transmission within 24 hours, finds new research led at Georgia State University. The study, published in Nature Microbiology, used a ferret model to test the effect of the drug on suppressing the spread of the virus. They found that the infected ferrets with SARS-CoV-2 and treated with Molnupiravir did not transmit the virus to any other ferrets co-housed with them. In contrast, those ferrets treated with placebo infected all other ferrets in close contact. The researchers believe that the ferrets are a relevant transmission model because they rapidly spread SARS-CoV-2 but do not generally develop severe disease, which resembles the spread of COVID-19 in young adults. This drug is now in advanced Phase 2/3 clinical trials for the treatment of COVID-19. DOI:10.1038/s41564-020-00835-2

Research led at McGill University has identified specific proteins that may make certain groups of people and animals more vulnerable to COVID-19. The research team found that animals, such as humans, cats and dogs, have two cysteine amino acids that form a special disulfide bond held together by an oxidizing cellular environment and this disulfide bond creates an anchor for SARS-CoV-2. They predict that a greater cellular oxidation in the elderly and in those with chronic health conditions creates an environment that allows more virus replication and advanced disease. In the animals resistant to the virus, like pigs and cows, one of those two cysteine amino acids is missing and thus no disulfide bond could form or anchor for the virus. The researchers suggest disrupting the oxidizing environment that keeps these disulfide bonds intact with antioxidants to decrease severity of COVID-19. This study is published in Computational and Structural Biotechnology Journal. DOI:10.1016/j.csbj.2020.11.016

Industry News

The University of California (UC) Riverside is the recipient of a 2021 UC Multicampus Research Programs and Initiatives (MRPI) award to fund the UC Coronavirus Assembly Research Consortium. This four-year project will aim to understand the factors contributing to the formation of coronaviruses, specifically SARS-CoV-2. UC Riverside will be joined by UC Merced and UC Davis with the goal to find ways to disrupt viral assembly and investigate the roles of structural proteins in SARS-CoV-2 formation using a multidisciplinary approach. The team will also explore the impact of some drugs on the assembly process. Press Release

Longenesis has announced the release of its product Curator, which is a platform that enables biomedical data sharing to a wide scientific audience without compromising the privacy of patients. The company has already collaborated with more than 20 clinical institutions, patient organizations, biobanks, genomic sequencers, and digital health startups across several countries. The new platform provides an opportunity for clinical investigators to showcase the scope of data that could be used for research while protecting patient privacy. Of note, the Latvian Biomedical Research and Study Center (BMC) is one collaborator that aims to accelerate COVID-19 research and has established a cohort of over 500 COVID-19 patients that includes various types of samples and detailed characterization of each clinical case. Press Release