Peptidase PepP is a novel virulence factor ofCampylobacter jejunicontributing to murine campylobacteriosis

Mechanisms of host-pathogen interactions resulting in immunopathological responses upon humanCampylobacter jejuniinfection are not completely understood, but the recent availability of murine infection models mimicking key features of campylobacteriosis helps solving this dilemma. During a screen for proteases expressed byC. jejuni, we identified a peptidase of the M24 family as a potential novel virulence factor, which was named PepP. The gene is strongly conserved in variousCampylobacterspecies. A constructed deletion mutant Delta pepPofC. jejunistrain 81-176 grew as efficiently compared to isogenic wild-type (WT) orpepPcomplemented bacteria. To shed light on the potential role of this protease in mediating immunopathological responses in the mammalian host, we perorally challenged microbiota-depleted IL-10(-/-)mice with these strains. All strains stably colonized the murine gastrointestinal tract with comparably high loads. Remarkably,pepPdeficiency was associated with less severe induced malaise, with less distinct apoptotic and innate immune cell responses, but also with more pronounced proliferative/regenerative epithelial cell responses in the large intestine at d6 post-infection. Furthermore, pro-inflammatory mediators were lower in the colon, ileum, and mesenteric lymph nodes of mice that had been challenged with the Delta pepPmutant compared to the WT orpepPcomplemented strains. This also held true for extra-intestinal organs including liver, kidneys, and lungs, and, strikingly, to systemic compartments. Taken together, protease PepP is a novel virulence determinant involved in mediating campylobacteriosis. The finding that apoptosis in the colon is significantly diminished in mice infected with thepepPmutant highlights the epithelial layer as the first and main target of PepP in the intestine.