Phosphatidic acid-mediated binding and mammalian cell internalization of the Vibrio cholerae cytotoxin MakA

Aftab Nadeem, Athar Alam, Eric Toh, Si Lhyam Myint, Zia ur Rehman, Tao Liu, Marta Bally, Anna Arnqvist, Hui Wang, Jun Zhu, Karina Persson, Bernt Eric Uhlin and Sun Nyunt Wai

PLOS Pathogens, 2021, vol. 17, issue 3, 1-34

Abstract: Vibrio cholerae is a noninvasive intestinal pathogen extensively studied as the causative agent of the human disease cholera. Our recent work identified MakA as a potent virulence factor of V. cholerae in both Caenorhabditis elegans and zebrafish, prompting us to investigate the potential contribution of MakA to pathogenesis also in mammalian hosts. In this study, we demonstrate that the MakA protein could induce autophagy and cytotoxicity of target cells. In addition, we observed that phosphatidic acid (PA)-mediated MakA-binding to the host cell plasma membranes promoted macropinocytosis resulting in the formation of an endomembrane-rich aggregate and vacuolation in intoxicated cells that lead to induction of autophagy and dysfunction of intracellular organelles. Moreover, we functionally characterized the molecular basis of the MakA interaction with PA and identified that the N-terminal domain of MakA is required for its binding to PA and thereby for cell toxicity. Furthermore, we observed that the ΔmakA mutant outcompeted the wild-type V. cholerae strain A1552 in the adult mouse infection model. Based on the findings revealing mechanistic insights into the dynamic process of MakA-induced autophagy and cytotoxicity we discuss the potential role played by the MakA protein during late stages of cholera infection as an anti-colonization factor.Author summary: Vibrio cholerae is the cause of cholera, an infectious disease causing watery diarrhea that can lead to fatal dehydration. The bacteria can readily adapt to different environments, such as from its natural aquatic habitats to the human digestive system. Recently, we reported a novel V. cholerae cytotoxin, MakA that functions as a potent virulence factor in C. elegans and zebrafish. Here we identified phosphatidic acid as a lipid target for MakA interaction with mammalian cells. This interaction promoted macropinocytosis resulting in the formation of an endomembrane-rich aggregate in intoxicated cells that ultimately lead to activation of autophagy. Importantly, data from bacterial colonization in a mouse infection model suggested that MakA might act as an anti-colonization factor of V. cholerae, presumably expressed during later stage(s) of infection. MakA might be explored as a new target for diagnostics and therapeutic developments against V. cholerae infections. Our findings will contribute to further understanding of the virulence, colonization and post-infection spread of V. cholerae.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:plo:ppat00:1009414

DOI: 10.1371/journal.ppat.1009414

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