Research Article: Norovirus interactions with the commensal microbiota

Date Published: September 6, 2018

Publisher: Public Library of Science

Author(s): Meagan E. Sullender, Megan T. Baldridge, Richard C. Condit.


Partial Text

Human norovirus (HNoV) is the leading cause of epidemic nonbacterial gastroenteritis worldwide, causing an acute diarrheal infection and occasionally chronic infection in immunocompromised individuals. Mouse and tissue culture models utilizing murine norovirus (MNoV) have allowed for interrogation of viral mechanisms of infection and pathogenesis. Here, we outline the interactions between the commensal microbiota of the intestine and norovirus and their implications (Fig 1).

Due to the fact that HNoV cannot readily grow in mice and, until recently, has not been culturable in vitro, the use of MNoV has provided robust animal and tissue culture model systems, which allow for mechanistic studies of an orthologous pathogen [1–4]. The MNoV model system allows for the merging of basic mechanistic principles of infection and replication from cell culture systems to pathogenesis in a host system that is both genetically malleable and affordable.

A large and diverse population of commensal microbes, consisting of bacteria, viruses, fungi, and parasites, reside within the intestinal lumen. NoV, being an enteric pathogen, encounters and interacts with members of this community, resulting in outcomes beneficial or detrimental to the host. HNoV has been found to interact directly with commensal (Enterobacter cloacae) and pathogenic (Clostridium difficile) bacterial species via the viral capsid and histo-blood group antigen (HGBA)-like carbohydrates expressed on bacterial surface membranes [12,13]. In addition, both HNoV and MNoV have been reported to bind sialic acid residues, which can be expressed on bacteria, suggesting that MNoV could also interact directly with the enteric microbiota [4,14].

The host intestinal immune system is highly regulated by a complex interplay of various lymphoid tissues, immune cells, cytokines, and their receptors [21–23] and possesses three distinct layers: mucus, epithelia, and lamina propria. In the small intestine, mucus-secreting goblet cells and antimicrobial peptide-secreting Paneth cells form the mucosal barrier that segregates commensal bacteria from the intestinal epithelia [24]. Intestinal epithelial cells directly interact with and survey the gut environment in coordination with innate lymphoid cells, which communicate with the immune system via secretion of cytokines and chemokines [24–26]. Dendritic cells ferry antigen from the lumen across the epithelial barrier to draining lymph nodes and mucosal lymphoid tissues in the lamina propria [27], and innate inflammatory signals and other luminal signals activate T- and B-cell responses [26]. These interacting layers play a large role in maintaining the microbiota and host immune system in homeostasis as well as regulating infection, inflammation, and autoimmunity.

Other enteric viruses, including rotavirus and poliovirus, have been found to depend on enteric bacteria to infect, similar to MNoV [28,29]. Commensal bacteria act as a proviral factor during poliovirus infection, as antibiotic treatment results in mice being less susceptible to infection and a reduced viral load in the intestine [28]. The mechanism underlying this involves viral particles binding to bacterial lipopolysaccharide, causing enhanced host cell receptor binding and virion stability [28,30]. Paradoxically, microbial depletion was found to increase antibody responses against rotavirus, which may contribute to enhanced viral clearance during antibiotic treatment [29].

While it is clear that the microbiome plays a significant role in both infectious and noninfectious diseases alike, much remains unknown about the exact mechanisms of action. FMTs have proven to be an effective treatment for Clostridium difficile (C. diff) infection and treatment-resistant irritable bowel syndrome (IBS) and may have potential in inflammatory bowel diseases [35]. It is likely that different underlying mechanisms contribute to the efficacy of these treatments; for example, specific bile acids regulated by intestinal bacteria are critical for resistance to C. diff infection [36,37]. Targeted administration of efficacious microbes would be ideal to prevent disease, and we are just beginning to identify the specific bacterial species that may regulate diseases from multiple sclerosis to diabetes to norovirus.