Vibrio cholerae at the Intersection of Immunity and the Microbiome

Abstract

Vibrio cholerae is a noninvasive pathogen that colonizes the small intestine and produces cholera toxin, causing severe secretory diarrhea. Cholera results in long lasting immunity, and recent studies have improved our understanding of the antigenic repertoire of V. cholerae Interactions between the host, V. cholerae, and the intestinal microbiome are now recognized as factors which impact susceptibility to cholera and the ability to mount a successful immune response to vaccination. Here, we review recent data and corresponding models to describe immune responses to V. cholerae infection and explain how the host microbiome may impact the pathogenesis of V. cholerae In the ongoing battle against cholera, the intestinal microbiome represents a frontier for new approaches to intervention and prevention.

Keywords: Vibrio cholerae; cholera; immune response; innate immunity; microbiome; vaccine.

FIG 1

Cholera toxin (CT) and the O-specific polysaccharide (OSP) are the two dominant V. cholerae antigens. Remarkably, following infection in an area of endemicity, more than 75% of the antibodies derived from clonally expanded plasmablasts targeted either CT or the OSP. CT antibodies target both the A and B subunits and may block toxin binding (A) or activity (B), yet the persistence of circulating antitoxin antibodies does not appear to confer long lasting immunity to cholera. OSP-specific antibodies target the bacterial outer membrane and confer protection. Several mechanisms have been proposed, including agglutination (C) and motility inhibition (D) or other effector functions which may entrap V. cholerae before it reaches the mucosal surface, such as activation of neutrophil extracellular traps.

FIG 2

Interactions between the gut microbiota, their metabolites, V. cholerae, and the small intestinal environment. (A) After V. cholerae survives the acidic gastric environment, the pathogen enters the small intestinal gut lumen, where both bile (green) and mucus (yellow) signal to V. cholerae to express the virulence factors that cause symptomatic infection. Mucus coats the villi and acts as a diffusion barrier, and V. cholerae uses flagellar motion to traverse the inner and outer mucus layers. During this journey V. cholerae encounters the resident gut microbes and their metabolites. After reaching the intestinal epithelial crypts, V. cholerae forms biofilms (shown as fibrous mats of organisms) to adhere to the epithelial surface. (B and C) When encountering the mucus layer, the V. cholerae type VI secretion system (T6SS) is activated. This system operates as a contractile organelle that extends from V. cholerae to make contact with neighboring organisms to translocate toxic effectors. T6SS activity can be suppressed by metabolites of cholic acid formed by gut microbiota that process bile (green and red curved arrow). (D) Autoinducer AI-2 (yellow) is produced by some commensal gut microbes and can induce quorum-sensing responses in V. cholerae. The presence of autoinducers indicate to V. cholerae a high density of organisms, resulting in reduced expression of virulence genes that enable colonization and cholera toxin production, and activation of genes that promote exit from the host, such as increased flagellar motion. (E) Bacteriophage specific to V. cholerae (vibriophage) can infect and lyse large numbers of organisms rapidly, drastically reducing V. cholerae populations.