Research ArticleCORONAVIRUS

TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes

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Science Immunology  13 May 2020:
Vol. 5, Issue 47, eabc3582
DOI: 10.1126/sciimmunol.abc3582

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Smothering fecal-oral coronavirus spread

Besides respiratory symptoms, diarrhea is one of the other commonly observed disease manifestations in patients with COVID-19. Zang et al. used organoid cultures of epithelial lining cells from human small and large intestine as an in vitro model system to study SARS-CoV-2 entry and replication in enterocytes. Mature enterocytes expressing the highest levels of the angiotensin-converting enzyme 2 (ACE2) viral receptor were susceptible to productive infection. Two related membrane-bound serine proteases, TMPRSS2 and TMPRSS4, enhanced virus entry into enterocytes. While a subset of patients with COVID-19 shed high levels of viral RNA in feces, experiments examining the effect of simulated human colonic fluid on the virus suggest that shed virus is rapidly inactivated during transit through the colon, strongly suppressing the potential for further spread of the infection through a fecal-oral route.


Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19. However, it is unclear whether SARS-CoV-2 replicates in the human intestine and contributes to possible fecal-oral transmission. Here, we report productive infection of SARS-CoV-2 in ACE2+ mature enterocytes in human small intestinal enteroids. Expression of two mucosa-specific serine proteases, TMPRSS2 and TMPRSS4, facilitated SARS-CoV-2 spike fusogenic activity and promoted virus entry into host cells. We also demonstrate that viruses released into the intestinal lumen were inactivated by simulated human colonic fluid, and infectious virus was not recovered from the stool specimens of patients with COVID-19. Our results highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.

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