COVID-19: TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes.

COVID-19: TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes.
Spencer EA, Heneghan C.

Published on July 10, 2020

Reference Zang R, Castro MFG, McCune BT et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Science Immunology  13 May 2020: Vol. 5, Issue 47, eabc3582 2020
Study type
Country USA
Setting Laboratory
Funding Details NIH grants, VA Merit grant, the Defense Advanced Research Project Agency, the Lawrence C. Pakula MD IBD Innovation Fund and unrestricted funds from Washington University School of Medicine.
Transmission mode Orofecal
Exposures Gastrointestinal Tract

Bottom Line

In a laboratory study, human enterocytes expressing high ACE2 receptor levels could support infection with SARS-CoV-2. However, the virus is rapidly inactivated in the GI tract, and no infectious virus was obtained from stool samples from COVID-19 patients.

Evidence Summary

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, facilitated SARS-CoV-2 spike fusogenic activity and promoted virus entry into enterocytes.

Viruses released into the intestinal lumen were rapidly inactivated by simulated human colonic fluid. 

Infectious virus was not recovered from the stool specimens of patients with COVID-19.

What did they do?

This laboratory study 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. The authors also tested ten fecal samples from patients with COVID-19 using a cell-based assay to determine if any infectious virus was present. 

Study reliability

This is a laboratory-based experimental study and needs to be considered in conjunction with observational epidemiological data.

Clearly defined setting Demographic characteristics described Follow-up length was sufficient Transmission outcomes assessed Main biases are taken into consideration
Yes N/A N/A N/A N/A

What else should I consider?

A subset of patients with COVID-19 shed high levels of viral RNA in feces. Compared with rotavirus, SARS-CoV-2 lost infectivity in the low pH simulated gastric fluid at 10 min after incubation. There was residual SARS-CoV-2 virus in the simulated human small intestinal fluid that contained biological surfactants (components of the bile,) including taurocholic acid sodium salt and lecithin.

The heavy glycosylation of SARS-CoV-2 S protein might confer some stability against the enzymatic digestion and bile salt solubilization in the GI tract. [Zhang Y, Chin A]

The study observed syncytia formation in human enteroids.  

  • Viral protein that mediates fusion of an infected cell with neighbouring cells leads to the formation of multi-nucleate enlarged cells called syncytia. syncytia are the result of the expression of a viral fusion protein at the host cell membrane during viral replication.

This results may have implications for virus cell-cell spread and evasion of antibody neutralization. [Schiffer T].


Zhang Y et al. Site-specific N-glycosylation characterization of recombinant SARS-CoV-2 spike proteins using high-resolution mass spectrometry. bioRxiv 2020.03.28.013276.. 29 March 2020.

Chin A   Stability of SARS-CoV-2 in different environmental conditions. Lancet Microbe 1, e10 (2020).

Schiffner T. Cell-to-cell spread of HIV-1 and evasion of neutralizing antibodies. Vaccine 31, 5789–5797 (2013).

About the authors

Carl Heneghan

Carl is Professor of EBM & Director of CEBM at the University of Oxford. He is also a GP and tweets @carlheneghan. He has an active interest in discovering the truth behind health research findings

Elizabeth Spencer

Dr Elizabeth Spencer; MMedSci, PhD. Epidemiologist, Nuffield Department for Primary Care Health Sciences, University of Oxford.