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TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes
Ruochen Zang1, Maria Florencia Gomez Castro1, Broc T McCune1
1Department 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.
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.
Insights
SARS-CoV-2 can productively infect human intestinal cells, but the virus released is inactivated in the colon, suggesting limited fecal-oral transmission. This research explores the intestine's role in COVID-19 progression.
Area of Science:
- Virology
- Gastroenterology
- Cell Biology
Background:
- Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are common in COVID-19 patients.
- The role of the human intestine in SARS-CoV-2 replication and potential fecal-oral transmission remains unclear.
Purpose of the Study:
- To investigate the potential for SARS-CoV-2 replication in the human intestine.
- To determine if the intestine contributes to fecal-oral transmission of SARS-CoV-2.
Main Methods:
- Utilized human small intestinal enteroids to model intestinal infection.
- Assessed the role of ACE2 and serine proteases (TMPRSS2, TMPRSS4) in virus entry.
- Tested the infectivity of SARS-CoV-2 in simulated human colonic fluid and stool specimens.
Main Results:
- SARS-CoV-2 productively infected ACE2-expressing mature enterocytes in human intestinal enteroids.
- TMPRSS2 and TMPRSS4 expression facilitated viral spike protein fusogenic activity and cell entry.
- Released SARS-CoV-2 was inactivated by simulated colonic fluid, and no infectious virus was found in patient stool.
Conclusions:
- The human intestine is a potential site for SARS-CoV-2 replication.
- While the intestine can be infected, viral inactivation in the colon limits fecal-oral transmission.
- Intestinal SARS-CoV-2 replication may contribute to local/systemic illness and disease progression.
