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

Here’s a detailed summary of the study “TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes”:

Study Overview

  • Title: TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes
  • Authors: Ruochen Zang, Maria Florencia Gomez Castro, et al.
  • Published: Sci. Immunol. 2020


  • Objective: Understanding whether SARS-CoV-2 replicates in the human intestine and contributes to fecal-oral transmission.
  • Background: Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are common in COVID-19 patients, raising questions about the role of the intestine in infection and disease progression​​.

Methods and Findings

  1. Infection of Intestinal Enteroids
    • SARS-CoV-2 infects human intestinal enteroids, specifically targeting ACE2+ mature enterocytes.
    • Higher ACE2 expression in the small intestine suggests a significant role in the fecal-oral transmission of the virus​​.
  2. Role of Serine Proteases in Infection
    • TMPRSS2 and TMPRSS4, mucosa-specific serine proteases, facilitate the virus’s entry by cleaving the spike protein and enhancing membrane fusion.
    • These proteases increase the infectivity of SARS-CoV-2, particularly in gut epithelial cells​​.
  3. Virus Replication and Release
    • SARS-CoV-2 actively replicates in ACE2+ human mature enterocytes.
    • The virus is predominantly released apically, suggesting potential fecal shedding in COVID-19 patients​​.
  4. Virus Inactivation in GI Tract
    • SARS-CoV-2 is rapidly inactivated in the human gastrointestinal (GI) tract, especially by components in the simulated human colonic fluid.
    • Viral RNA may not be infectious when shed in feces, reducing the likelihood of fecal-oral transmission​​.


  • Implications: The study indicates that while the intestine can be a site of SARS-CoV-2 replication, contributing to local and systemic illness, the rapid inactivation of the virus in the colon may limit fecal-oral transmission risk.
  • Clinical Observations: Some COVID-19 patients exhibit gastrointestinal symptoms before respiratory symptoms, suggesting the gut might play a role in systemic disease progression.
  • Future Research: Further studies are needed to fully understand the gut’s role in infection and disease spread, especially considering the unique stability of the SARS-CoV-2 spike protein​​.


This study provides crucial insights into the pathogenesis of COVID-19, highlighting the intestine’s potential role in virus replication and the mechanisms facilitating this process. It also offers a better understanding of the infection’s transmission dynamics, particularly concerning fecal-oral transmission risks.

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