Potential intestinal infection and faecal-oral transmission of SARS-CoV-2

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to more than 200 countries and regions globally. SARS-CoV-2 is thought to spread mainly through respiratory droplets and close contact. However, reports have shown that a notable proportion of patients with coronavirus disease 2019 (COVID-19) develop gastrointestinal symptoms and nearly half of patients confirmed to have COVID-19 have shown detectable SARS-CoV-2 RNA in their faecal samples. Moreover, SARS-CoV-2 infection reportedly alters intestinal microbiota, which correlated with the expression of inflammatory factors. Furthermore, multiple in vitro and in vivo animal studies have provided direct evidence of intestinal infection by SARS-CoV-2. These lines of evidence highlight the nature of SARS-CoV-2 gastrointestinal infection and its potential faecal-oral transmission. Here, we summarize the current findings on the gastrointestinal manifestations of COVID-19 and its possible mechanisms. We also discuss how SARS-CoV-2 gastrointestinal infection might occur and the current evidence and future studies needed to establish the occurrence of faecal-oral transmission.

Fig. 1. Evidence of SARS-CoV-2 intestinal infection.

This figure shows the putative mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) intestinal infection. Angiotensin-converting enzyme 2 (ACE2) is mainly expressed on the brush border of enterocytes in the ileum and colon. Cell entry by SARS-CoV-2 (1) begins with the binding of spike (S) proteins to ACE2. Host cell transmembrane serine protease 2 (TMPRSS2) cleaves the S protein. Subsequently, the cell membrane fuses with the viral membrane and SARS-CoV-2 genomic RNA is released into the cytoplasm. Based on human intestinal organoid studies, SARS-CoV-2 primarily infects enterocytes but not goblet cells. The double membrane structure produced by virus replication (2) can be observed in the infected cells and the virus protein can be detected in the endoplasmic reticulum (ER). Newly assembled viral particles were released predominantly from the apical side into the lumen. The detection of subgenomic mRNA (sgmRNA) can serve as evidence of active viral replication in the intestine. SARS-CoV-2 infection activates an interferon-mediated immune response (3) in human organoids. Levels of the intestinal epithelial cell-specific inflammatory factor IL-18, which is activated by inflammasomes, have been shown to increase in patients with severe coronavirus disease 2019 (COVID-19). However, how SARS-CoV-2 triggers immune response in the gut in humans is not yet well understood, including the role of inflammatory factors caused by intestinal infection and their contribution to cytokine release syndrome (CRS), and requires further investigation. The histological examination of human intestinal samples revealed that lymphocytes and inflammatory cells infiltrated the lamina propria (4). Patients with diarrhoea exhibited increased faecal calprotectin levels, released mainly by infiltrated neutrophils. However, whether intestinal infiltrations of T cells, B cells, macrophages and neutrophils as well as of their secreted cytokine and IgA are correlated with disease severity is still unknown. SARS-CoV-2 infection altered the gut microbiota community structure (5). The enrichment of opportunistic pathogens and the depletion of beneficial commensals was observed in patients with COVID-19. These changes were correlated with the expression of inflammatory factors in the serum of these patients. However, whether the microbiota profile can predict the occurrence of CRS and whether modulation of the microbiota can resolve CRS need further study. IEL, intraepithelial lymphocyte.

Fig. 2. The potential faecal–oral transmission of SARS-CoV-2.

The exact faecal–oral transmission route is not yet established for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); green boxes show confirmed findings, whereas orange boxes depict open questions. High viral loads were found in the faecal samples of patients with coronavirus disease 2019 (COVID-19) and diarrhoea. However, the number of patients with COVID-19 that shed infectious viruses (but not viral RNA) in faeces remains unknown. In several cases, infectious virus was isolated in faeces and an in vitro study reported 1–2 survival days of SARS-CoV-2 in faeces. Thus, the virus might possibly contaminate sewage, water, and food supplies and possibly contaminate bathroom sites via faecal–aerosol transmission. Consistent with this hypothesis, viral RNA was detected in sewage and on toilet seats, flush buttons and door handles. Moreover, the detection of infectious virus in packaged seafood was reported in China. However, the research on virus titre in faecal fomites is still lacking. Whether the virus titres in faecal fomites are of sufficient concentration and infectivity for subsequent transmission remains unknown. Moreover, SARS-CoV-2 can tolerate human small intestinal fluid but rapidly loses infectivity in gastric fluid within 10 minutes. It remains unclear whether the virus can survive during food intake or whether it is protected by sputum, which is a previously reported by-pass mechanism of Middle East respiratory syndrome coronavirus and influenza.