Abstract
While infectious agents have typical host preferences, the noninvasive enteric bacterium Vibrio cholerae is remarkable for its ability to survive in many environments, yet cause diarrheal disease (cholera) only in humans. One key V. cholerae virulence factor is its neuraminidase (VcN), which releases host intestinal epithelial sialic acids as a nutrition source and simultaneously remodels intestinal polysialylated gangliosides into monosialoganglioside GM1. GM1 is the optimal binding target for the B subunit of a second virulence factor, the AB5 cholera toxin (Ctx). This coordinated process delivers the CtxA subunit into host epithelia, triggering fluid loss via cAMP-mediated activation of anion secretion and inhibition of electroneutral NaCl absorption. We hypothesized that human-specific and human-universal evolutionary loss of the sialic acid N-glycolylneuraminic acid (Neu5Gc) and the consequent excess of N-acetylneuraminic acid (Neu5Ac) contributes to specificity at one or more steps in pathogenesis. Indeed, VcN was less efficient in releasing Neu5Gc than Neu5Ac. We show enhanced binding of Ctx to sections of small intestine and isolated polysialogangliosides from human-like Neu5Gc-deficient Cmah-/- mice compared to wild-type, suggesting that Neu5Gc impeded generation of the GM1 target. Human epithelial cells artificially expressing Neu5Gc were also less susceptible to Ctx binding and CtxA intoxication following VcN treatment. Finally, we found increased fluid secretion into loops of Cmah-/- mouse small intestine injected with Ctx, indicating an additional direct effect on ion transport. Thus, V. cholerae evolved into a human-specific pathogen partly by adapting to the human evolutionary loss of Neu5Gc, optimizing multiple steps in cholera pathogenesis.
Highlights
Cholera is a life-threatening, human-specific disease caused by the noninvasive enteric bacterium Vibrio cholerae that affects millions of people worldwide [1]
Ingestion of food or water contaminated with the bacterium Vibrio cholerae can cause fatal diarrheal disease in humans, but not in other mammals exposed to the bacterium
Humans lost the ability to produce a kind of sialic acid called Neu5Gc during our evolution and the glycans of our small intestine are different from most other mammals
Summary
Cholera is a life-threatening, human-specific disease caused by the noninvasive enteric bacterium Vibrio cholerae that affects millions of people worldwide [1]. Bacteria that survive passage through the acidic milieu of the stomach can colonize and multiply on the surface of the small intestinal epithelium [2] and induce severe watery diarrhea This main symptom of the disease leads to loss of electrolytes and blood volume depletion, and can be fatal if the individual is not rehydrated rapidly [2]. The rise in cAMP causes intense secretion of chloride ions through the cystic fibrosis transmembrane conductance regulator (CFTR) as well as inhibition of electroneutral sodium chloride absorption [8]. These events are followed by passive water flow in response to osmotic gradients, resulting in profuse diarrhea [9]. CtxA further induces epithelial cell barrier disruption by inhibiting exocyst-mediated trafficking of host proteins that make up the intercellular junctions of epithelial cells, a mechanism that may act in parallel with Cl− secretion to drive the pathophysiology of cholera [10]
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