Abstract
Vi capsular polysaccharide (Vi) is a major virulence factor of human typhoid-causing pathogen Salmonella enterica serovar Typhi (S. Typhi). It distinguishes S. Typhi from closely related non-typhoidal Salmonella serovars such as S. Typhimurium which do not normally cause systemic infection in humans. Vi not only forms a capsule around S. Typhi but it is also readily released from this pathogen. We have previously reported that Vi targets prohibitin to inhibit cellular responses activated through immune receptors. Here, we show that engagement of membrane prohibitin with Vi prevents Salmonella-induced activation of small Rho-family GTPases, Rac1, and Cdc42, and suppresses actin cytoskeletal rearrangements resulting in reduced invasion and highly subdued inflammatory responses. Cells infected with S. Typhimurium in the presence of Vi show poor activation of NF-kB and MAP-kinase pathways of intracellular signaling. Treatment with Vi brings about redistribution of Rac-1, prohibitin, and ganglioside GM1 in membrane raft domains. Vi-mediated interference with activation of Rho-family GTPases represents a previously unrecognized mechanism by which S. Typhi can limit its invasion and alarming of the host.
Highlights
Pathogenic serovars of bacterium Salmonella enterica such as S
Since Salmonella invasion is mediated through induction of actin cytoskeletal rearrangements, we reasoned that interaction of Vi with prohibitin might modulate the ability of epithelial cells to enable bacterial invasion
The results presented here demonstrate that targeting of prohibitin with Vi brings about changes in the membrane that prevent activation of GTPases, Rac1, and Cdc42 (Figure 2A), which play a critical role in initiating invasion and invasion-dependent inflammatory responses during infection of epithelial cells with Salmonella (Hardt et al, 1998)
Summary
Pathogenic serovars of bacterium Salmonella enterica such as S. Typhi to evade TLR-driven host defense responses from intestinal epithelial cells (IECs) and monocytes (Sharma and Qadri, 2004; Raffatellu et al, 2005; Garg and Qadri, 2010) Our studies with these cell types and T cells showed that Vi suppresses immune responses by directly targeting membrane associated prohibitin family of molecules, which are highly conserved ubiquitously expressed proteins involved in cell signaling, regulation of mitochondrial respiratory chain complexes, and gene expression (Sharma and Qadri, 2004; Garg and Qadri, 2010; Santhanam et al, 2014; Peng et al, 2015). We present evidence that engagement of membrane prohibitin with Vi inhibits Salmonella-induced activation of GTPases, Rac, and Cdc, thereby reducing bacterial intake and suppressing secretion of cytokines
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.
