Sara Cherry PhD, John W. Eckman Professor of Medical Science and a Professor of Microbiology in the Department of Microbiology at the Perelman School of Medicine of the University of Pennsylvania, Professor, Pathology and Laboratory Medicine, Scientific Director of the High-throughput screening core and Director of the Program for Chemogenomic Discovery, University of Pennsylvania
David Schultz PhD, Technical Director of the High-throughput screening core, University of Pennsylvania
Maayan Levy PhD, Assistant Professor of Microbiology, University of Pennsylvania
Christoph Thaiss PhD, Assistant Professor, Department of Microbiology, University of Pennsylvania
This study will directly inform how therapeutics can best be positioned into clinical trials aimed at clearing potential SARS-CoV-2 reservoirs in individuals with Long COVID. The project team is employing tissue models of human organ systems along with chemical & genetic screening technologies to reveal molecular insights into SARS-CoV-2 infection of diverse tissues. Antiviral or immunomodulatory drugs are administered to the tissue models to determine what therapeutics – or combinations of therapeutics – best target SARS-CoV-2 in these different tissue types. Because the gastrointestinal tract is a likely site of SARS-CoV-2 reservoir in Long COVID, the project team will begin by studying SARS-CoV-2 infection and response to therapeutics in gastrointestinal cellular and organoid models. The gastrointestinal tract also harbors an extensive microbiome that produces metabolites capable of impacting SARS-CoV-2 infection. The team will consequently use a small molecule library of microbial metabolites (~700) to screen for metabolites that may either suppress or enhance SARS-CoV-2 infection of gastrointestinal tissue.
A second phase of the study will expand this research into models of other cell types and organ systems implicated in SARS-CoV-2 pathogenesis and/or Long COVID. These include liver, heart, brain, and immune cells. Because SARS-CoV-2 has been shown to impact endothelial cell biology, the team will use endothelial cell models from distinct body sites (e.g., blood-brain barrier, umbilical endothelial cells, cardiac endothelial cells) in their research. In all cell or tissue models (including gastrointestinal), transcriptional profiling will be performed to explore how the diverse cell types respond to SARS-COV-2 infection or viral antigen stimulation. The team will determine if these responses are similar across viral variants and if homeostasis can be restored by co-treating the tissues with drugs that block the altered response.
A central possibility for Long COVID development is that patients with the condition do not fully clear the SARS-CoV-2 virus after acute infection. Instead, the virus may persist in patient tissue or nerves in a “reservoir” where it continues to produce antigens (proteins) that provoke the immune system. If a SARS-CoV-2 reservoir contributes to the Long COVID disease process it is important to determine: 1) which tissues, cell types, or body sites are most likely to harbor a SARS-CoV-2 reservoir 2) what treatment strategies can best be used to target the SARS-CoV-2 virus and successfully clear the reservoir.
This project’s team has decades of experience studying emerging viruses and identifying antiviral strategies to control their activity. They have been screening and studying antivirals active against SARS-CoV-2 for the past two years and have identified combinations of antivirals that successfully targeted the virus in respiratory tract tissue models. The current project will expand on this research and use additional models of human tissue – including from the gastrointestinal tract, liver, blood vessels, and brain – to characterize SARS-CoV-2’s activity in these sites and determine what drug combinations best target the virus in each anatomical location.