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.
Highlights
Vibrio cholerae, the causative agent of the disease cholera, is an extracellular facultative human pathogen, with aquatic and intestinal life cycles [1,2]
Vibrio cholerae is the cause of cholera, an infectious disease causing watery diarrhea that can lead to fatal dehydration
The MakA protein caused lethal effect on C. elegans and zebrafish, it has remained unclear how the MakA protein may interact with mammalian host cells
Summary
The causative agent of the disease cholera, is an extracellular facultative human pathogen, with aquatic and intestinal life cycles [1,2]. V. cholerae O1 and O139 serogroups express the cholera toxin (CT), a main virulence factor, and the toxin co-regulated pilus (TCP), which are responsible for diarrhea and intestinal colonization, respectively. Regulation of host signaling pathways by bacterial pathogens is critical for colonization and replication within, or in the close vicinity of, eukaryotic host cells. To achieve the best possible colonization condition, many bacterial species have evolved a variety of molecular mechanisms that include direct delivery of effector proteins to the host cell membrane [6]. Most intracellular bacteria use a special mechanism to invade non-phagocytic cells, characterized by induction of macropinocytosis, an endocytic pathway that involves actin-mediated membrane ruffling and engulfment that leads to the formation of macropinosomes [8,9,10]. Macropinocytosis is initiated via actin polymerization, upon hyper-stimulation of growth factor receptors leading to activation of phosphoinositide 3-kinase (PI3K) and small GTPases [11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
