Enteric Viral Co-Infections: Pathogenesis and Perspective

Abstract

Enteric viral co-infections, infections involving more than one virus, have been reported for a diverse group of etiological agents, including rotavirus, norovirus, astrovirus, adenovirus, and enteroviruses. These pathogens are causative agents for acute gastroenteritis and diarrheal disease in immunocompetent and immunocompromised individuals of all ages globally. Despite virus-virus co-infection events in the intestine being increasingly detected, little is known about their impact on disease outcomes or human health. Here, we review what is currently known about the clinical prevalence of virus-virus co-infections and how co-infections may influence vaccine responses. While experimental investigations into enteric virus co-infections have been limited, we highlight in vivo and in vitro models with exciting potential to investigate viral co-infections. Many features of virus-virus co-infection mechanisms in the intestine remain unclear, and further research will be critical.

Keywords: co-infection; co-infection models; enteric virus; viral pathogenesis.

Figure 1

Potential consequences of enteric viral co-infections. (a) Co-infection of multiple viral strains in a single cell facilitates the recombination and generation of novel strains. (b) Extracellular vesicles containing multiple virions of a single virus type, one means of co-infecting new cells. Whether co-infection with unrelated viruses could lead to co-packaging is unknown. (c) An example of enteric viral interference, wherein murine AstV infection inhibits murine NoV infection of tuft cells via IFN-λ production.

Figure 2

In vivo and in vitro co-infection study models. In vivo models for enteric virus studies include mouse (murine NoV, AstV, and RV), fly (Drosophila C virus, Flock House virus), pig (human RV, human NoV, and porcine epidemic diarrhea virus), C. elegans (Orsay virus) and non-human primate (human RV and NoV, simian RV, and rhesus enteric caliciviruses) models with physiological experimental read-outs. In vitro models that could be used for enteric co-infection studies include organoids/enteroids and immortalized cell lines for detailed analyses in simplified systems. Illustration created using BioRender (BioRender.com).