The Role of Ion Transporters in the Pathophysiology of Infectious Diarrhea

Abstract

Every year, enteric infections and associated diarrhea kill millions of people. The situation is compounded by increases in the number of enteric pathogens that are acquiring resistance to antibiotics, as well as (hitherto) a relative paucity of information on host molecular targets that may contribute to diarrhea. Many forms of diarrheal disease depend on the dysregulation of intestinal ion transporters, and an associated imbalance between secretory and absorptive functions of the intestinal epithelium. A number of major transporters have been implicated in the pathogenesis of diarrheal diseases and thus an understanding of their expression, localization, and regulation after infection with various bacteria, viruses, and protozoa likely will prove critical in designing new therapies. This article surveys our understanding of transporters that are modulated by specific pathogens and the mechanism(s) involved, thereby illuminating targets that might be exploited for new therapeutic approaches.

Keywords: ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; CDI, Clostridium difficile infection; CFTR, cystic fibrosis transmembrane conductance regulator; CLCA1, chloride channel accessory 1; CT, cholera toxin; CXCR2, C-X-C motif chemokine receptor 2; DRA, down-regulated in adenoma; Diarrhea; ENaC, epithelial sodium channel; EPEC, enteropathogenic Escherichia coli; ETEC, enterotoxigenic Escherichia coli; Enteric Pathogen; Epithelium; EspG, Escherichia coli secreted protein G; GPR39, G-protein coupled receptor 39; Ion Transport; KCC, potassium-chloride cotransporter; LPA, lysophosphatidic acid; LT, heat-labile toxin; NHE, sodium/hydrogen exchanger; NHERF2, sodium/hydrogen exchanger regulatory factor 2; NKCC, sodium-potassium-2 chloride cotransporter; ORT, oral rehydration therapy; PKC, protein kinase C; SGLT1, sodium-glucose cotransporter 1; SLC, solute carrier; ST, heat-stabile toxin; TNF, tumor necrosis factor; Tcd, Clostridium difficile toxin; ZnR, zinc sensing receptor; cAMP, adenosine 3′,5′-cyclic monophosphate.

Figure 1

Localization of absorptive ion transporters (discussed in text) in the small intestine and colon, and their regulation by pathogens or their secreted toxins. The figure is not intended to imply that the illustrated transporters are necessarily expressed in the same cells. Note particularly that ENaC is present only in the distal colon. The red bars indicate inhibitory effects. The effect shown for Salmonella on the Na⁺, K⁺ ATPase consists of mislocalization to the apical membrane that would be expected to disrupt absorptive transport; however, note that a stimulatory effect of a Salmonella effector on the ATPase also has been reported (not shown). CT, cholera toxin; DRA, down-regulated in adenoma; ENaC, epithelial sodium channel; EPEC, enteropathogenic E. coli; KCC1, potassium chloride cotransporter-1; NHE, sodium hydrogen exchanger; NSP4, Rotavirus non-structural protein 4; SGLT1, sodium glucose cotransporter-1; ST, heat-stable toxin of E. coli; LT, heat-labile toxin of E. coli; TcdB, C. difficile toxin B.

Figure 2

Chloride secretory mechanism in the small intestine and colon, and regulation of its constituent transporters by pathogens or their secreted toxins. The green arrows and red bars represent stimulatory and inhibitory effects, respectively. CaCC, calcium-activated chloride channel; ACE, accessory cholera enterotoxin; TDH, thermostable direct hemolysin of V parahemolyticus; NSP4, rotavirus nonstructural protein-4; KCNN4, calcium-activated potassium channel; KvLQT1/KCNE3, cAMP-activated potassium channel.