Researchers find TMPRSS2 and TMPRSS4 enable SARS-CoV-2 infection of digestive system

A new study has suggested that SARS-CoV-2, the virus responsible for the COVID-19 pandemic, may not spread via faecal-to-oral transmission, but can infect the human digestive system. The research was conducted by an international team led by scientists at the Washington University School of Medicine, US. 

According to the authors, their analysis is the first of its kind to combine the study of human gut cells in simulated human gastrointestinal (GI) fluids with assays of faecal samples from patients with COVID-19. The researchers did not detect any infectious SARS-CoV-2 virus in stool specimens taken from 10 patients with COVID-19, although they did detect high levels of viral RNA in three of these samples.

The results also suggest the protein-digesting enzyme TMPRSS4 – related to TMPRSS2, which has been implicated in previous SARS-CoV-2 infectivity studies – can facilitate viral entry into gut cells. Blocking the two enzymes may therefore be a promising treatment strategy, the authors say, especially since a TMPRSS2 inhibitor already exists in camostat, a drug approved in Japan to treat pancreatitis.

Seeking to explain why diarrhoea and other GI symptoms have been observed in roughly 50 percent of COVID-19 patients so far, Ruochen Zang and colleagues exposed gut epithelial cells taken from healthy human patients to a chimera of the vesicular stomatitis virus (VSV) and SARS-CoV-2 – a hybrid structure commonly used to increase the safety of studying contagious viral pathogens – as well as wild-type SARS-CoV-2. The researchers found that both the chimeric and wild-type viruses can rapidly infect and replicate in human gut cells with help from TMPRSS4 and TMPRSS2 and can drive the formation of syncytia, fusions of infected and healthy neighbouring cells.

However, in additional experiments, a fluorescently tagged wild-type SARS-CoV-2 quickly lost infectivity when exposed to simulated human colonic fluid, becoming undetectable after 24 hours. Simulated small intestinal fluids did not inactivate SARS-CoV-2 as quickly, despite the presence of a bile acid with detergent activity. The researchers caution that their limited faecal sample size, drawn from 10 patients with COVID-19, prevents them from definitively ruling out faecal-oral transmission of COVID-19. In future work, they plan to assess whether underlying conditions, such as inflammatory bowel disease, may affect clinical outcomes of SARS-CoV-2 infection.

The study was published in Science.