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Principal Investigator: MATTHEW AARON CIORBA
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $625,575
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Although coronavirus disease 2019 (COVID-19) is primarily defined as a respiratory illness, up to 50% of
patients experience clinical gastrointestinal symptoms, including nausea, abdominal pain, and diarrhea. We
recently found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes
COVID-19, infects and replicates in human small bowel intestinal epithelial cells (IECs). However, the molecular
mechanisms by which SARS-CoV-2 drives gastrointestinal pathology and how that impacts the mucosal immune
responses and systemic diseases remain unclear.
In this proposal, our overall objectives are to better define the cellular signaling of SARS-CoV-2 interactions
with IECs, enteric immune responses, and microbiome in the context of health or inflamed intestines (i.e.,
inflammatory bowel disease (IBD)). Our preliminary data suggest that compared to normal COVID-19 patients,
those with IBD who have higher expression of cathepsin L in IECs prior to infection, supported higher viral loads.
Our central hypothesis is that SARS-CoV-2 induces a distinctive intestinal pathology and mucosal immune
response that is shaped by host factors (IBD), luminal factors (bile salts and microbiome), and therapeutics.
Specifically, using healthy and IBD-derived organoids, COVID-19 patient fecal samples, SARS-CoV-2 variants,
and a highly tractable and innovative intraluminal injection mouse model, we aim to (1) define the host factors
and cellular mechanisms involved in SARS-CoV-2 infection of normal and IBD epithelium, (2) determine the
impact of intestinal SARS-CoV-2 infection on intestinal immune response and colitis, and (3) define the
environmental factors that influence intestinal infection with SARS-CoV-2.
With extensive and collaborative expertise in intestinal biology, virology, and mucosal immunology (including
IBD), we expect to address mechanistically interesting and clinically important questions regarding SARS-CoV-
2 enteric infection, immune responses, and intestinal pathology. We anticipate that the knowledge derived from
this study will further our understanding of SARS-CoV-2 interactions with the epithelial and immune cells to
explain COVID-19 GI symptoms with or without IBD. We also expect the new information gained from this project
will expand our understanding of acute and chronic gastrointestinal pathology and symptoms of COVID-19,
provide novel strategies to mitigate COVID-19 associated GI diseases, and create a foundational knowledge
and tool set for deeper investigations into COVID-19 and potentially pathogenic and emerging coronaviruses of
the future.
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severity><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 severity><COVID19 virus><CTSL Protein><CV-19><Cathepsin L><Causality><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cells><Chronic><Clinical><CoV emergence><CoV-2><CoV2><Colitis><Colon><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Data><Delta variant><Diarrhea><Digestive Tract><Disease><Disorder><Dysfunction><Emesis><Endosomes><Enteral><Enteric><Enterocytes><Environmental Factor><Environmental Risk Factor><Epithelial Cells><Epithelium><Etiology><Feces><Functional disorder><Future><GI Tract><GI microbiome><Gamma variant><Gastrointestinal Diseases><Gastrointestinal Physiology><Gastrointestinal Tract><Gastrointestinal tract structure><Genetic><Genotype><Granulomatous Enteritis><Groups at risk><Health><Homeostasis><Host Factor><Host Factor Protein><Household><Human><Immune><Immune 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