The intersection between host-pathogen interactions and metabolism during Vibrio cholerae infection

Abstract

Vibrio cholerae (V. cholerae), the etiological agent of cholera, uses cholera toxin (CT) to cause severe diarrheal disease. Cholera is still a significant cause of mortality worldwide with about half of all cholera cases and deaths occurring in children under five. Owing to the lack of cost-effective vaccination and poor vaccine efficacy in children, there is a need for alternative preventative and therapeutic strategies. Recent advances in our knowledge of the interplay between CT-induced disease and host-pathogen metabolism have opened the door for investigating how modulation of intestinal metabolism by V. cholerae during disease impacts host intestinal immunity, the gut microbiota, and pathogen-phage interactions. In this review article, we examine recent progress in our understanding of host-pathogen interactions during V. cholerae infection and discuss future work deciphering how modulation of gut metabolism during cholera intersects these processes to enable successful fecal-oral transmission of the pathogen.

Figure 1

Host–pathogen interactions and metabolism during Vibrio cholerae infection. During infection, Vibrio cholerae colonizes the ileum of the SI and produces high levels of CT, which activates adenylate cyclase, increasing cellular levels of cAMP. Increased concentrations of cAMP lead to activation of PKA, which phosphorylates and activates the CFTR to secrete chloride ions out of epithelial cells, resulting in an electrolyte imbalance and massive water loss. Increased cAMP and activation of PKA leads to metabolic changes in target cells, which are predicted to lead to the secretion of host-derived LCFAs, L-lactate, and glycerol. During early stages of colonization (left side), V. cholerae encounters host factors, including bile acids, which act as signaling molecules to activate ToxT-dependent virulence factor expression. V. cholerae has to overcome components of the innate immune system, including antimicrobial proteins and secretory antibodies, such as IgA, after penetration of the mucus layer. The microbiota in the SI likely imposes ‘colonization resistance’ that V. cholerae overcomes by unknown mechanisms. The gut microbiota also may compete with V. cholerae for host-derived nutrients during CT-induced disease that the pathogen overcomes by evolutionary adaptation of the diseased gut as well as its T6SS. CT-induced disease leads to increased secretion of host defense proteins, which the pathogen overcomes by unknown mechanisms. CT-induced modulation of host metabolism promotes the luminal growth of V. cholerae during infection by acquisition of host-derived nutrients, including LCFAs, L-lactate, and heme. Host-derived L-lactate that is produced during CT-induced disease may play a role in ‘lactylation’ of immune cells in the gut. Furthermore, we propose that CT-induced growth of V. cholerae plays a role in pathogen susceptibility to phage during infection that the pathogen overcomes by deploying phage defense systems. Altogether, these complex chain events that lead to CT-mediated disease and successful replication of V. cholerae have been selected for during the evolution of the pathogen in order to ensure fecal–oral transmission of a new host.