Abstract
Salmonella enterica serovar Typhimurium (S. Typhimurium) uses two-component regulatory systems (TCRS) to respond to stimuli in the local microenvironment. Upon infection, the Salmonella TCRSs PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB) are activated by environmental signals in the intestinal lumen and within host cells. TCRS-mediated gene expression results in lipopolysaccharide (LPS) modification and cationic antimicrobial peptide resistance. The PmrA-regulated pmrHFIJKLM operon mediates 4-amino-4-deoxy-L-arabinose (Ara4N) production and attachment to the lipid A of LPS. A ΔpmrF S. Typhimurium strain cannot produce Ara4N, exhibits increased sensitivity to cationic antimicrobial peptide (CAMP)-mediated killing, and attenuated virulence in mice upon oral infection. CAMPs are predicted to play a role in elimination of Salmonella, and may activate PhoPQ and PmrAB in vivo, which could increase bacterial resistance to host defenses. Competition experiments between wild type (WT) and ΔpmrF mutant strains of S. Typhimurium indicated that selection against this mutant first occurs within the intestinal lumen early during infection. However, CRAMP and active cryptdins alone are not responsible for elimination of Ara4N-deficient bacteria in vivo. Investigation into the early immune response to ΔpmrF showed that it differed slightly from the early immune response to WT S. Typhimurium. Further investigation into the early immune response to infection of Peyer’s patches suggests a role for IL-13 in the attenution of the ΔpmrF mutant strain. Thus, prominent CAMPs present in the mouse intestine are not responsible for the selection against the ΔpmrF strain in this location, but limited alterations in innate immune induction were observed that affect bacterial survival and virulence.
Highlights
Bacteria must evade a powerful arsenal of host immune cells and antimicrobial factors to survive in vivo
In addition to playing a direct role in bacterial killing, several cationic antimicrobial peptide (CAMP) have immunomodulatory properties and help regulate other host immune responses that participate in elimination of invading pathogens [2,3,4]
The findings described here promote a better understanding of the genetic basis of Salmonella pathogenesis, the role of LPS modifications in resistance to CAMPs and the arsenal of host innate immune responses induced upon bacterial infection
Summary
Bacteria must evade a powerful arsenal of host immune cells and antimicrobial factors to survive in vivo. Salmonella enterica use two-component regulatory systems (TCRSs), including PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB), to modify gene expression in response to the local microenvironment [5,6,7]. Typhimurium) sensing of environmental signals through the inner membrane-bound sensor kinase PhoQ results in activation of the PhoPQ regulon, including genes whose products mediate lipopolysaccharide (LPS) modification [8,9]. Salmonella TCRS-mediated detection of specific environmental factors, which may include CAMPs, during infection likely allows bacteria to mediate rapid changes in gene expression that promote survival in the presence of these and other host immune defenses
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