The PmrAB System-inducing Conditions Control Both Lipid A Remodeling and O-antigen Length Distribution, Influencing the Salmonella Typhimurium-Host Interactions*

Background: Salmonella Typhimurium LPS structure is regulated by the PmrAB, PhoPQ, and RcsCDB systems. Results: Wzzst is required for lipid A modifications. PbgE2 and PbgE3 control formation of short O-antigen region. Conclusion: PmrAB system is the master regulator of LPS remodeling, modulating genes that modify lipid A, core, and O-antigen. Significance: Salmonella exhibits complex mechanisms to modulate its LPS, which influences host interaction. The Salmonella enterica serovar Typhimurium lipopolysaccharide consisting of covalently linked lipid A, non-repeating core oligosaccharide, and the O-antigen polysaccharide is the most exposed component of the cell envelope. Previous studies demonstrated that all of these regions act against the host immunity barrier. The aim of this study was to define the role and interaction of PmrAB-dependent gene products required for the lipopolysaccharide component synthesis or modification mainly during the Salmonella infection. The PmrAB two-component system activation promotes a remodeling of lipid A and the core region by addition of 4-aminoarabinose and/or phosphoethanolamine. These PmrA-dependent activities are produced by activation of ugd, pbgPE, pmrC, cpta, and pmrG transcription. In addition, under PmrA regulator activation, the expression of wzzfepE and wzzst genes is induced, and their products are required to determine the O-antigen chain length. Here we report for the first time that Wzzst protein is necessary to maintain the balance of 4-aminoarabinose and phosphoethanolamine lipid A modifications. Moreover, we demonstrate that the interaction of the PmrA-dependent pbgE2 and pbgE3 gene products is important for the formation of the short O-antigen region. Our results establish that PmrAB is the global regulatory system that controls lipopolysaccharide modification, leading to a coordinate regulation of 4-aminoarabinose incorporation and O-antigen chain length to respond against the host defense mechanisms.

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