| Vibrio cholerae is a Gram-negative bacterium that is responsible for the diarrheal disease cholera. Despite its historical description as a non-inflammatory secretory diarrhea, cholera has recently been appreciated as having an acute pro-inflammatory phase. Inflammatory processes associated with natural infection by V. cholerae are known to be enhanced in recipients of live attenuated vaccine strains. The resultant inflammatory symptomology is known as vaccine reactogenicity, and is a major barrier to the development of improved cholera vaccines. Using animal and in vitro model systems, we uncover interactions of secreted toxins of V. cholerae with the host innate immune system.;Studies in an adult mouse model of infection indicate that inflammation induced in the small intestine is neutrophilic in nature, and is enhanced by cholera toxin. Cholera toxin, in addition to its well-studied role in inducing fluid secretion, enhances colonization and virulence by synergistically inciting inflammation with neutrophils. The MARTX, hemolysin, and hemagglutinin (HA)/protease accessory toxins induce increased expression of IL-6, IL-10, and MIP-2 in the small intestine, but in addition to provoking host innate immune responses, appear to establish persistent small intestine colonization in part by inhibiting bacterial killing by neutrophils.;Studies in human monocytic THP-1 cells indicate that the secreted toxins of V. cholerae also enhance inflammation by activating multiple inflammasomes, leading to the secretion of pro-inflammatory cytokine IL-1beta and lysis of host cells. V. cholerae of different biotypes have differing abilities to activate inflammasomes, depending on their toxin repertoire. The pore-forming hemolysin toxin potently activates the NLRP3 inflammasome, whereas the MARTX and HA/Protease toxins have no role in inflammasome activation. CT activates a canonical ASC-dependent inflammasome through the action of its A-subunit, as well as a non-canonical inflammasome pathway dependent on the B-subunit in concert with intracellular LPS. It is also observed that inflammasome activation correlates with clinical disease severity as it pertains to newly emerged Altered El Tor strains that cause severe disease and candidate vaccine strains that are associated with vaccine reactogenicity.;Altogether, these studies provide evidence for pro-inflammatory effects of V. cholerae toxins, which have implications both for pathogenicity and development of improved vaccines. |
