Introduction
SARS-CoV-2 exhibits an extra-pulmonary tropism, with up to 70% of COVID-19 patients experiencing at least one gastrointestinal (GI) symptom. Persistent viral presence has been observed in intestinal biopsies months after the virus has been cleared from the respiratory tract, which has been implicated in the development of long COVID symptoms. Despite these observations, the dynamics of SARS-CoV-2 infection within the intestine, as well as its potential to act as a viral reservoir and source of ongoing pathogenesis, remain largely unknown.
Aims & Methods
We recently established a robust mouse model to study the dynamics of intestinal SARS-CoV-2 infection by exposing the distal ileum of mice through ventral laparotomy and administering the virus directly into the lumen.
Results
In wild-type (WT) C57Bl/6 mice, after perfusion, viral RNA was detected throughout the GI tract at 7 days post infection (dpi), not only at the site of initial infection, but also in other regions such as the esophagus, stomach, duodenum, jejunum, colon, and rectum. Moreover, viral RNA was also found in extra-intestinal sites, including the salivary gland, liver, and brain. In Stat1-/- mice with impaired type I, II, and III interferon signaling, the levels of viral RNA as well as nucleocapsid antigens in the GI tract were 10 to 100 times higher than those in WT mice. Virus also successfully disseminated to systemic organs such as the heart, lung, kidney, brain, and spleen. Viral shedding in feces was observed from 3 to 7 dpi in Stat1-/- mice but not WT mice. Notably, rapid secretory diarrhea was observed in these mice, marking the first instance of diarrhea induced by SARS-CoV-2 infection in a mouse model. Additional studies are ongoing to further characterize these findings, including the assessment of the timing of viral replication, titration of infectious viruses, detailed histological analysis, and immunological profiling.
Conclusion
These results emphasize the usefulness of this mouse model in exploring the mechanisms underlying the impact of SARS-CoV-2 on the intestines locally and systemically. The study also underscores the critical role of interferon signaling in restricting intra-intestinal replication and preventing the virus from spreading to other organs. This has important clinical implications, particularly for individuals taking JAK inhibitor medications, which could affect the interferon response and potentially increase susceptibility to more severe outcomes from SARS-CoV-2 infection.
Disclosure
M.S.D. is a consultant for Inbios, Vir Biotechnology, Ocugen, Topspin Therapeutics, GlaxoSmithKline, Moderna, and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions, and Moderna.