Project Team

Sara Cherry PhD: Professor, Pathology and Laboratory Medicine, Scientific Director of the High-throughput screening core and Director of the Program for Chemogenomic Discovery, UPENN

Maayan Levy, PhD: Assistant Professor of Microbiology, UPENN who has a longstanding interest in gastrointestinal infections and LongCOVID.

Christoph Thaiss PhD: Assistant Professor, Department of Microbiology, UPENN who has been studying complex physiological responses and has performed extensive analysis of diverse tissues infected with SARS-CoV-2

Benjamin Abramoff MD: Director of the Post-COVID Assessment and Recovery Clinic, Physical Medicine and Rehabilitation Department, UPENN has a large cohort of long COVID patients along with clinical data.

Daniel Streblow, PhD: (Collaborator) Associate Professor, VGTI-Vaccine and Gene Therapy Institute, Molecular Microbiology and Immunology, Oregon Health Sciences University

Project Summary:

Project lead Dr. Sara Cherry

This project combines experiments in humans, non-human primates, and mice to determine mechanisms by which SARS-CoV-2 reservoir in the gut contributes to Long COVID. More specifically, the project team is: 1) Measuring SARS-CoV-2 activity over time in Long COVID patients’ stool samples 2) Examining SARS-CoV-2 shedding, pathobiology, and impact on the gut microbiome in non-human primates, and 3) Developing a mouse model of gut infection to study acute vs. chronic SARS-CoV-2 infection.

Project background:

A major area of Long COVID research centers on a failure of patients to fully clear the SARS-CoV-2 virus after acute infection. Instead, the virus can persist in patient tissue in a “reservoir” where it may drive inflammation and symptoms. For a number of reasons, the gastrointestinal tract is a likely SARS-CoV-2 reservoir site in at least a subset of Long COVID patients. First, the intestinal tract can be readily infected by SARS-CoV-2 experimentally. Second, autopsy studies demonstrate viral persistence in gastrointestinal tissue. Third, high levels of viral RNA can be detected in the stool and in sewage systems suggesting shedding from the gut. Fourth, viral RNA can be detected in the stool from patients suffering from Long COVID.

However, questions remain about how SARS-CoV-2 gut reservoirs impact the Long COVID disease process. These include: 1) What fraction of Long COVID patients harbor viral RNA in their stool? Is this persistent over time? 2) Are there particular symptoms associated with the presence of a viral reservoir in the gut? 3) Are there changes in the microbiome or microbial metabolites associated with the virus or its proteins in the stool? 4) Is there viral evolution associated with chronic infection of the gut?

This project team is working to answer these questions via three central studies:

Defining SARS-CoV-2 gut reservoir over time in Long COVID patients: The team is characterizing SARS-CoV-2 sequence, replication, and impact on the gut microbiome and metabolites in stool samples provided by Long COVID patients. These analyses will provide essential information for future studies including patient stratification, new biomarkers, and clinical trial candidates.

Defining SARS-CoV-2 shedding and pathobiology in a longitudinal cohort of non-human primates. The team is following a group of non-human primates infected with SARS-CoV-2 over time, with a range of samples including stool and blood collected at various timepoints. These samples are analyzed for viral RNA levels, replication, the sequence of the viral strain, and the impact of SARS-CoV-2 on the microbiome and metabolites of the gut. Gut tissue is also examined. These studies will provide essential information for future studies in human patients.

Develop a mouse model of GI infection to explore acute vs chronic infections. A major gap in Long COVID is a lack of a small animal model that replicates parts of the disease process. The team has generated a mouse model prone to SARS-CoV-2 gut infection. They are using this model to explore shedding from the gut over time, viral variants that may arise, and to define the tissues and cell types that produce virus.