Human evolutionary loss of epithelial Neu5Gc expression and species-specific susceptibility to cholera

Frederico Alisson-Silva, Janet Z. Liu, Sandra L. Diaz, Lingquan Deng, Melanie Gareau, Ronald Marchelletta, Xi Chen, Victor Nizet, Nissi Varki, Kim E. Barrett, Ajit Varki

Research output: Contribution to journalArticle

3 Scopus citations

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 AB5cholera 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.

Original languageEnglish (US)
Article numbere1007133
JournalPLoS Pathogens
Volume14
Issue number6
DOIs
StatePublished - Jun 1 2018

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Alisson-Silva, F., Liu, J. Z., Diaz, S. L., Deng, L., Gareau, M., Marchelletta, R., Chen, X., Nizet, V., Varki, N., Barrett, K. E., & Varki, A. (2018). Human evolutionary loss of epithelial Neu5Gc expression and species-specific susceptibility to cholera. PLoS Pathogens, 14(6), [e1007133]. https://doi.org/10.1371/journal.ppat.1007133