Is SARS-CoV-2 Also an Enteric Pathogen With Potential Fecal-Oral Transmission? A COVID-19 Virological and Clinical Review

Abstract

In as few as 3 months, coronavirus disease 2019 (COVID-19) has spread and ravaged the world at an unprecedented speed in modern history, rivaling the 1918 flu pandemic. Severe acute respiratory syndrome coronavirus-2, the culprit virus, is highly contagious and stable in the environment and transmits predominantly among humans via the respiratory route. Accumulating evidence suggest that this virus, like many of its related viruses, may also be an enteric virus that can spread via the fecal-oral route. Such a hypothesis would also contribute to the rapidity and proliferation of this pandemic. Here we briefly summarize what is known about this family of viruses and literature basis of the hypothesis that severe acute respiratory syndrome coronavirus-2 is capable of infecting the gastrointestinal tract and shedding in the environment for potential human-to-human transmission.

Figure 1

A simplified diagram of the SARS-CoV-2 replication cycle (with potential pharmacological inhibitors under investigation depicted at respective steps). The virion and its associated viral proteins are shown schematically at the top. The structure of the S trimer is depicted. (1) Interaction between viral S protein and host ACE2 mediates virus binding to the host cell. (2) S protein is cleaved by host serine proteases, such as TMPRSS2, allowing the fusion of viral membrane with the host membrane and single-stranded RNA (ssRNA) (+) genome release into the cytoplasm. (3) Transcription and translation of viral proteins from genomic and subgenomic RNAs. (4) Replication occurs within the replicative membranous compartment, where and new ssRNA(+) are synthesized. (5) Virus assembly at the endoplasmic reticulum (ER), the intermediate compartments, and/or the Golgi complex. (6) Release of new virions by exocytosis. E, envelope protein; HE, hemagglutinin-esterase glycoprotein; M, membrane protein; N, nucleocapsid protein.

Figure 2

Coronaviruses and their associated diseases. (A) Common human and animal CoVs are shown in relative genetic distance by phylogenetic analysis (not drawn to scale). Coronaviruses can be divided into 4 genera: alpha, beta, gamma, and deltacoronaviruses (division shown on the branches of the phylogenetic tree). BCoV, bovine coronavirus; CCoV, canine coronavirus; FECoV, feline enteric coronavirus; FIPV, feline infectious peritonitis virus; IBV, infectious bronchititis virus; PEDV, porcine epidemic diarrhea virus; PHEV, porcine hemagglutinating encephalomyelititis virus; TCoV, turkey coronavirus; TGEV, transmissible gastroenteritis virus. HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2 are human CoVs. Hundreds of bat CoVs (not shown on the phylogenetic tree here) have been isolated and many of them are closely related to these human and animal CoVs, suggesting that bats are the original source of these viruses. SARS-CoV has been proposed to jump from bat to civet to human, SARS-CoV-2 from bat to pangolin to human, and MERS-CoV from bat to camel to human. The main hosts and involvement of organ systems of these CoVs are shown in (B).

Figure 3

Modes of transmission of SARS-CoV-2 in humans. The primary mode of human-to-human transmission is airborne for SARS-CoV-2. The virus likely first infects the respiratory epithelium and spreads to the rest of the body via circulation. Other potential organs of involvement include intestine, hepatobiliary system, heart, kidney, or central nervous system, many of which express high levels of ACE2, the main receptor for viral entry. Whether the virus can directly infect the intestine bypassing the respiratory system is unknown. Either way, the virus may infect, replicate, and shed from the enterocytes and possibly hepatocytes/cholangiocytes and be excreted as fecal materials into the environment, contaminating water and food supplies. Whether the virus can be transmitted directly to other humans via fecal–oral route or infect household pets, like cats, or wildlife first before passing to humans remain key questions.