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

Sci Immunol. 2020 May 13;5(47):eabc3582. doi: 10.1126/sciimmunol.abc3582.

Ruochen Zang ¹, Maria Florencia Gomez Castro ¹, Broc T McCune ¹, Qiru Zeng ¹, Paul W Rothlauf ¹, Naomi M Sonnek ¹, Zhuoming Liu ¹, Kevin F Brulois ¹, Xin Wang ¹, Harry B Greenberg ¹, Michael S Diamond ¹, Matthew A Ciorba ¹, Sean P J Whelan ¹, Siyuan Ding ²

Affiliations

1 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA. Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao, China. Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, USA. Program in Virology, Harvard Medical School, 200 Longwood Ave, Boston, MA, USA. Department of Medicine, Division of Gastroenterology, Washington School of Medicine, St. Louis, MO, USA. Department of Pathology, Stanford School of Medicine, Stanford, CA, USA. VA Palo Alto Health Care System, Department of Veterans Affairs, Palo Alto, CA, USA. Department of Medicine, Division of Gastroenterology and Hepatology, and Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA, USA. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
2 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA. Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao, China. Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, USA. Program in Virology, Harvard Medical School, 200 Longwood Ave, Boston, MA, USA. Department of Medicine, Division of Gastroenterology, Washington School of Medicine, St. Louis, MO, USA. Department of Pathology, Stanford School of Medicine, Stanford, CA, USA. VA Palo Alto Health Care System, Department of Veterans Affairs, Palo Alto, CA, USA. Department of Medicine, Division of Gastroenterology and Hepatology, and Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA, USA. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. siyuan.ding@wustl.edu.

PMID: 32404436 DOI: 10.1126/sciimmunol.abc3582

Abstract

Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19 patients. 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 COVID-19 patients. 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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