Abstract
BackgroundCampylobacter jejuni has emerged as a leading cause of bacterial enterocolitis. The serine protease HtrA has been shown to be a pivotal, novel C. jejuni virulence factor involved in cell invasion and transmigration across polarised epithelial cells in vitro. However, the functional relevance of the htrA gene for the interaction of C. jejuni with the host immune system in the infant mouse infection model has not been investigated so far.ResultsHere we studied the role of C. jejuni htrA during infection of 3-weeks-old infant mice. Immediately after weaning, conventional wild-type mice were perorally infected with the NCTC11168∆htrA mutant (∆htrA) or the parental wild-type strain. Approximately one third of infected infant mice suffered from bloody diarrhea until day 7 post infection (p.i.), whereas colonic histopathological changes were rather moderate but comparable between the two strains. Interestingly, parental, but not ∆htrA mutant infected mice, displayed a multifold increase of apoptotic cells in the colonic mucosa at day 7 p.i., which was paralleled by higher colonic levels of pro-inflammatory cytokines such as TNF-α and IFN-γ and the matrix-degrading enzyme matrixmetalloproteinase-2 (MMP-2). Furthermore, higher numbers of proliferating cells could be observed in the colon of ∆htrA infected mice as compared to the parental wild-type strain. Remarkably, as early as 7 days p.i. infant mice also exhibited inflammatory changes in extra-intestinal compartments such as liver, kidneys and lungs, which were less distinct in kidneys and lungs following ∆htrA versus parental strain infection. However, live C. jejuni bacteria could not be found in these organs, suggesting the induction of systemic effects during intestinal infection.ConclusionUpon C. jejuni ∆htrA strain infection of infant mice, intestinal and extra-intestinal pro-inflammatory immune responses were ameliorated in the infant mouse model system. Future studies will shed further light onto the molecular mechanisms of host-pathogen interactions.
Highlights
Campylobacter jejuni has emerged as a leading cause of bacterial enterocolitis
Whereas the vast majority of C. jejuni infections is normally self-limiting in humans, post-infectious sequelae such as Guillain-Barré syndrome, Miller Fisher syndrome, Reiter’s syndrome and reactive polyarthritis might arise in rare cases [3,7]
Whereas HtrA family members were considered in the past to strictly act intracellularly in the bacteria, we recently discovered that HtrA is actively secreted into the extracellular environment where it cleaves cell surface adhesion proteins and tumor-suppressor E-cadherin [21,22,23]
Summary
The serine protease HtrA has been shown to be a pivotal, novel C. jejuni virulence factor involved in cell invasion and transmigration across polarised epithelial cells in vitro. A plethora of bacterial outer membrane proteins such as JlpA, CadF, FlpA, PEB1 among others has been shown to be involved in adhesion to epithelial cells [9,10,11,12,13], whereas CadF can induce the activation of small Rho GTPases, Rac and Cdc, which exert invasive properties in vitro [13,14,15,16] and in human ex vivo biopsies [17]. We and others have recently shown that the C. jejuni serine protease and chaperone HtrA (high temperature requirement A) displays a novel virulence factor [18,19,20,21]. HtrA gene deletion has been shown to result in defective E-cadherin shedding and compromised transmigration of C. jejuni across polarized epithelial cells in vitro [21]
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