New Virtual Reality Tool, Domestic Cats are SARS-CoV-2 Carriers, Combination Therapy Advances: COVID-19 Updates
November 20, 2020 I St. Jude discovers hyperinflammatory pathway, hepatitis C drugs are potential treatment, non-human primate model identifies features of virus, IL-10 production is a marker for severity, recommendations on re-use of data, molecular structure of key E-protein, and early antibody evolution predicts outcomes. Plus: Disrupting SKI complex prevents viral replication, why COVID-19 spares children, and how smoking causes more severe infection.
Research News
Two collaborative studies, published in the journal Emerging Microbes & Infections, show that domestic cats can be asymptomatic carriers of SARS-CoV-2, but pigs are not likely to be significant carriers of the virus. Researchers from Kansas State University conducted an in-depth study at the K-State Biosecurity Research Institute (BRI) and determined that domestic cats may not have obvious clinical signs of the virus, but they still shed the virus through their nasal, oral and rectal cavities and can spread it to other cats within two days. Authors of the study highlight its importance in understanding risks of animal to human transmission. DOI:10.1080/22221751.2020.1833687
St. Jude Children’s Research Hospital scientists have discovered the process behind the life-threatening hyperinflammatory immune response associated with COVID-19 and potential therapeutics to disrupt this process. In mice models, they determined a combination of two cytokines that triggered this inflammatory cell death pathway: TNF-alpha and IFN-gamma. Neutralizing antibodies against these cytokines are currently used to treat inflammatory diseases, and researchers found that treatment with these antibodies protected mice from death associated with SARS-CoV-2 infection and other inflammatory conditions caused by cytokine storm. These findings are published in Cell. DOI:10.1016/j.cell.2020.11.025
In a new study, published in JACC: Basic to Translational Research, researchers used publicly available gene expression data to determine how COVID-19 impacts cardiovascular tissue and endothelial cells. They determined that cardiorenal tissue and endothelial cells express higher or comparable levels of SARS-CoV-2 associated genes to those found in the lungs or airway epithelium, supporting the hypothesis that COVID-19 may infect the vasculature. DOI:10.1016/j.jacbts.2020.09.010
Research led at the University of Tennessee Health Science Center (UTHSC) has identified three drugs that can potentially be repurposed for treatment of COVID-19. Based on virtual and in vitro experiments conducted at the UTHSC Regional Biocontainment Laboratory (RBL), the researchers found zuclopenthixol (an antipsychotic drug), nebivolol (an antihypertensive drug), and amodiaquine (an older antimalarial) to be good candidates for future clinical trials. They found these three drugs to act similarly to hydroxychloroquine, in some cases safer, and efficacy may be improved with combination therapy using remdesivir. This research is published in ACS Pharmacology & Translational Science. DOI:10.1021/acsptsci.0c00131
In vitro combination therapy of remdesivir and human recombinant soluble ACE2 (hrsACE2) shows promising results for the treatment of COVID-19 in a new study led by researchers at Karolinska Institutet. The research group tested this drug combination in cell cultures and organoids and found a reduced viral load of SARS-CoV-2 and inhibited viral replication. They achieved these results with a relatively lose dose of each drug, which reduced toxicity and risk for potential side effects. The authors of this study, which is published in EMBO Molecular Medicine, hope these findings will lead to successful clinical trials for combination therapy. DOI:10.15252/emmm.202013426
New research led at UCLA reveals how smoking causes more severe COVID-19 infection in the airways. The research team used a model of airway tissue created from human stem cells that were donated from the lungs of five young, healthy nonsmokers and exposed the airway cultures to cigarette smoke. The group then infected the cigarette smoke exposed cultures with SARS-CoV-2, along with cultures that were not exposed to smoke. The researchers found that the cultures exposed to smoke had two to three times more infected cells and determined that the blocking of interferons due to smoking was the cause for this finding. This study is published in Cell Stem Cell. DOI:10.1016/j.stem.2020.11.010
SARS-CoV-2 specific antibodies likely provide protection against reinfection of the virus, according to new research from the University of Freiburg. The scientists examined characteristics of the SARS-CoV-2 specific T-cells and determined that they differentiate into memory T-cells that are comparable to the flu. The authors of the study, published in Nature Medicine, are confident that this immunological memory means that vaccines currently being tested will provide significant protection against COVID-19. DOI:10.1038/s41591-020-01143-2
Experiments led by researchers at the Department of Energy’s Oak Ridge National Laboratory have identified hepatitis C drugs with the potential to treat COVID-19. The team performed an X-ray study that revealed promising results for the hepatitis C drugs boceprevir and narlaprevir, which exhibited the ability to bind and inhibit the SARS-CoV-2 main protease that enables the virus to reproduce. The study also discovered the protease’s ability to change or adapt its shape according to the size and structure of the inhibitor molecule it binds to. This research is published in Structure, and the team suggests consideration of hepatitis C inhibitors as potential repurposing candidates for the treatment of COVID-19. DOI:10.1016/j.str.2020.10.007
A nonhuman primate model developed at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) has identified features of the SARS-CoV-2 virus that may help in vaccine development and treatment for COVID-19. The research team showed in this primate study that the virus causes vascular inflammation and that this persisted for 3 days following infection. They also confirmed immunosuppression as the viral load increased during the first 2 days of infection and observed rapid replication of the virus in the upper and lower respiratory tract for the first 2 days, followed by a rapid decrease with no viral activity detected 7 days post-infection. These findings are published in the Journal of Infectious Disease. DOI:10.1093/infdis/jiaa486
Vanderbilt University Medical Center researchers have uncovered why COVID-19 seems to spare children. The research team identified an enzyme, called TMPRSS2, that allows the virus to gain entry into airway epithelial cells and is found at lower levels in children. In the study, published in the Journal of Clinical Investigation, the researchers obtained and analyzed human lung specimens collected from donors of different ages and found that the expression of TMPRSS2 went up significantly with age. The team also analyzed autopsy samples for three patients who died from COVID-19 and found the virus in three types of cells that express the enzyme. Drugs that block TMPRSS2, which have been approved for the treatment of prostate cancer, are currently being tested clinically as a potential treatment for COVID-19. DOI:10.1172/JCI140766
Interleukin 10 (IL-10) production may act as a marker for severity of COVID-19, finds new research published in Clinical and Translational Immunology. A team of immunology experts examined immunological features associated with the development of severe COVID-19 disease by comparing the immune system response to COVID-19 in patients showing mild to moderate or severe symptoms, using a subset of healthy individuals as a control group. The researchers, surprisingly, found few differences in T cell response in the blood of severe COVID-19 patients when compared to the healthy individuals. They did, however, identify a significant increase in T cells producing IL-10 in patients with severe disease compared to the healthy group. The authors note that larger-scale studies are needed to confirm these findings. DOI:10.1002/cti2.1204
Researchers at the University of Maryland School of Medicine have identified new drug compounds to potentially treat novel coronaviruses, such as COVID-19. The study, published in PNAS, found that disrupting the SKI complex prevents the virus from replicating, which essentially destroys it. The team also identified compounds that target the SKI complex which not only inhibit coronaviruses, but also influenza and Ebola. The authors of the study hope these findings lead to development of new broad-spectrum antiviral drugs. DOI:10.1073/pnas.2012939117
Early antibody evolution may predict COVID-19 patient outcomes, according to new research published in Cell. The study used a systems serology approach to profile the antibody responses of 193 hospitalized COVID-19 patients and compared responses from patients with moderate and severe disease to those who died. Researchers found that all patients developed antibodies against the virus, but patients who passed away never fully developed an antibody response. In those died, there was a significant defect in the development of IgG antibodies and stunted development of the antibodies’ ability to strongly bind to Fc-receptors, which consequently never triggered a strong immune response against the virus. The team also found that of the survivors, the immune system recognized and targeted the S2 domain of the SARS-CoV-2 spike protein, suggesting a previous exposure to other coronaviruses and pre-existing immunity. DOI:10.1016/j.cell.2020.10.052
New research from Georgetown University Medical Center demonstrates the use of RNA molecules to successfully shut down the production of destructive proteins produced by COVID-19. The team showed that microRNAs (miRNAs) and silencing RNAs (siRNAs) can target messenger RNA inside a virus. SARS-CoV-2 uses messenger RNA to generate proteins essential for replication and infection. The authors of the study note that this ability to target the virus within cells, particularly through siRNA, could help shut the virus down. The researchers are working to aerosolize the RNA molecules to incorporate in an inhalable drug that would interfere with the production of the protein spikes associated with infectivity of the virus. This work is published in Gene Therapy. DOI:10.1038/s41434-020-00210-0
University of Bristol scientists have developed and demonstrated a new virtual (VR) reality tool, called Narupa, that allows researchers to virtually test COVID-19 drug candidates. In the study, published in the Journal of Chemical Information and Modeling, the team created a 3D model structure of the SARS-CoV-2 main protease (Mpro) and used interactive molecular dynamics in VR to visualize molecules binding to the enzyme in atomic detail. Their results showed that users were able to show how a drug molecule fits within the enzyme. The tool is an open source software framework that uses readily available VR equipment and enables virtual collaboration in the global fight against COVID-19. DOI:10.1021/acs.jcim.0c01030
The common D614G mutation may make SARS-CoV-2 more susceptible to a vaccine, finds a new study published in Science. Researchers of this study confirmed that this most common strain, which emerged in Europe, replicates and transmits quickly and efficiently but the mutation to the spike protein also makes it more sensitive to neutralizing antibody drugs. Hamster models investigating the original strain from China and the mutated strain showed that the mutated strain replicated about ten times faster and was more infectious, but the researchers did not find the mutated strain to cause more severe disease. The team explained that the D614G mutation also alters the spike protein in a way that creates a more vulnerable pathway to the virus’ core. DOI:10.1126/science.abe8499
Massachusetts Institute of Technology (MIT) scientists have discovered the molecular structure of a key protein found in the SARS-CoV-2 virus. This protein, named the envelope E protein, acts as an ion channel and plays an important role in viral replication and activation of the host cells’ inflammatory response. The MIT researchers also studied the binding sites of two drugs, amantadine and hexamethylene amiloride, that block the entrance of the E channel, but these drugs only bind weakly to the E protein. The authors of this study, published in Nature Structural and Molecular Biology, hope these findings help medicinal chemists to design new drugs that target this channel with high affinity. DOI:10.1038/s41594-020-00536-8
Researchers in China have developed a rhesus macaque model that mimics SARS-CoV-2 infection in humans via the nasal route. The study, published in PLOS Pathogens, revealed viral shedding in the nose and stool for up to 27 days and progression from mild disease to marked interstitial pneumonia, both of which resemble the manifestations of COVID-19 in humans. The research team also found that T-cells played an important role in viral disease progression and cytokine changes in the respiratory tract triggered inflammation, noting that treatments and vaccines should focus on these immune responses. DOI:10.1371/journal.ppat.1008949
A new study, published in PNAS, reveals models that detail binding and, for the first time, unbinding mechanisms that play key roles in the immune system response. The computational analysis shows the unbinding of peptides from the major histocompatibility complex (MHC) with atomic resolution. The research team found that in these secondary interactions, position 4 plays an important role in the stability of the complex and their model was able to predict the effect of mutations. The researchers believe that this work will have an impact on the fight against COVID-19, as the SARS peptide they investigated is very similar to the peptide in SARS-CoV-2, with the same binding pockets in positions 2, 4 and 9. DOI:10.1073/pnas.2007246117
Industry News
XPRIZE and Cognizant have announced a Pandemic Response Challenge that aims to safely reopen societies and restart economies through the power of data and artificial intelligence. Based on technology and AI models developed by Cognizant, and using data compiled by the Oxford COVID-19 Government Response Tracker, competing teams will build data-driven AI models that predict local COVID-19 transmission rates and prescribe intervention and measures to minimize infection rates, as well as negative economic impacts. This four-month competition will award a total prize of $500K at its conclusion. Press Release
In a special December issue, SLAS Discovery will feature research focusing on drug discovery efforts toward the COVID-19 pandemic. The issue will include four reviews that cover the commonly utilized approach of repurposing drugs to rapidly treat SARS-CoV-2, as well as targeting the virus using new vaccines and clinical drugs. The article, “High-Throughput Screening for Drugs that Inhibit Papain-Like Protease in SARS-CoV-2”, explores how an ultra-high throughput screening platform targeting PLPro was used to investigate over 13,000 clinically applicable drugs, and another article of original research tests drug-like ligands for their efficacy against the MAC domain of SARS2 Nsp3, a novel approach. Press Release
The December issue of SLAS Technology will feature a special collection of articles addressing COVID-19 and focuses on the advancing technological innovations being used to address the novel coronavirus. The special collection includes seven articles of original research, in addition to two reviews and the featured cover article, “Advances in Technology to Address COVID-19”. Press Release
The Governance Lab (GovLab) at the NYU Tandon School of Engineering has released recommendations for the re-use of data in response to the COVID-19 crisis. The guidance and a new Responsible Data Re-Use framework stem from The Data Assembly initiative in New York City. The GovLab co-hosted four months of remote deliberations with civil rights organizations, key data holders, and policymakers and this newly published release is the product of this combined effort to guide New York decision-makers on potential costs and benefits of re-using data while considering the sometimes contradictory needs of various stakeholders. Press Release
The Wellcome Sanger Institute and the COVID-19 Genomics UK (COG-UK) have received funding from the Department for Health and Social Care Testing Innovation Fund to expand whole genome sequencing of positive SARS-CoV-2 virus samples to track how COVID-19 is spreading and mutating. Since March 2020, COG-UK has generated more than 100,000 SARS-CoV-2 genomes, made available to the public and making up over 45 percent of the global total. The Sanger Institute has rapidly established new sequencing pipelines and developed supporting software to sequence and analyze the virus samples. The genomic data will be used to monitor the virus as new vaccines are deployed and identify any mutations that may impact vaccine efficacy. Press Release