Salmonella enterica Serovar Typhimurium CpxRA Two-Component System Contributes to Gut Colonization in Salmonella-Induced Colitis

Abstract

, a common cause of diarrhea, has to colonize the gut lumen to elicit disease. In the gut, the pathogen encounters a vast array of environmental stresses that cause perturbations in the bacterial envelope. The CpxRA two-component system monitors envelope perturbations and responds by altering the bacterial gene expression profile. This allows to survive under such harmful conditions. Therefore, CpxRA activation is likely to contribute to gut infection. However, the role of the CpxRA-mediated envelope stress response in-induced diarrhea is unclear. Here, we show that CpxRA is dispensable for the induction of colitis by serovar Typhimurium, whereas it is required for gut colonization. We prove that CpxRA is expressed during gut infection and that the presence of antimicrobial peptides in growth media activates the expression of CpxRA-regulated genes. In addition, we demonstrate that a Typhimurium strain lacking the gene is able to cause colitis but is unable to continuously colonize the gut. Finally, we show that CpxRA-dependent gut colonization requires the host gut inflammatory response, while DegP, a CpxRA-regulated protease, is dispensable. Our findings reveal that the CpxRA-mediated envelope stress response plays a crucial role in gut infection, suggesting that CpxRA might be a promising therapeutic target for infectious diarrhea.

Tat-exported peptidoglycan amidase-dependent cell division contributes to Salmonella Typhimurium fitness in the inflamed gut

“…To this end, we performed a CI experiment using the S . Tm invG ssaV avirulent strain, which is incapable of inducing the gut inflammation [ 47 ]. We first confirmed that a mutation of the invG gene had no effect on the cell division in vitr o ( S5 Fig ).…”

“…As S . Tm amiA and amiC expression is positively regulated by the CpxRA two-component system [ 57 ], the bacterial strains were grown under CpxRA-inducible conditions; i.e., high osmolarity (here, 0.5 M NaCl) [ 58 ] or the presence of antimicrobial peptide (here, 1 μg/ml polymyxin B) [ 47 , 59 ], and subjected to microscopy analysis. When grown in LB broth containing 0.5 M NaCl, in all cell configurations, the proportion of chains of GFP-expressing ssaV amiC and GFP-expressing ssaV amiA amiC strains were dramatically increased ( Fig 8A and 8B ).…”

“…Tm undergoes filamentous growth in vitro accompanied with changes of outer membrane integrity [ 68 ], osmotic stress may generally induce a cell division defect in this bacterium. Furthermore, the CpxRA envelope stress response, which is activated by high osmolarity and antimicrobial peptides [ 47 , 58 , 59 , 69 ], has been shown in turn to activate transcription of the amiA and amiC genes in response to periplasmic stress, which occurs in the inflamed gut [ 47 , 57 ], and contribute to S . Tm gut colonization during Salmonella -induced colitis [ 47 ].…”

“…Furthermore, the CpxRA envelope stress response, which is activated by high osmolarity and antimicrobial peptides [ 47 , 58 , 59 , 69 ], has been shown in turn to activate transcription of the amiA and amiC genes in response to periplasmic stress, which occurs in the inflamed gut [ 47 , 57 ], and contribute to S . Tm gut colonization during Salmonella -induced colitis [ 47 ]. These findings suggest that environmental stresses such as high osmolarity and antimicrobial peptide in the inflamed gut may elicit envelope perturbations of S .…”

Salmonella Pathogenicity Island 1 Is Expressed in the Chicken Intestine and Promotes Bacterial Proliferation

“…To first demonstrate that our reporter strain retained virulence and to characterize the expression of SPI-1 in the mouse intestinal tract, a well-defined animal model, we performed a competition assay between the fluorescent reporter and the otherwise isogenic wild-type (WT) S. Typhimurium ATCC 14028s in mice. Streptomycintreated C57BL/6 mice were orally inoculated with an equal mixture of the two strains, and bacterial colonization of the ilea, ceca, liver, and spleen was quantified at 2 days postinfection, a time by which robust inflammation is observed in this model (24)(25)(26). We found that our reporter strain retained full virulence, colonizing both the intestine and systemic sites similarly to the wild-type organism ( Fig.…”