Immunopathological properties of the Campylobacter jejuni flagellins and the adhesin CadF as assessed in a clinical murine infection model

Abstract

Background Campylobacter jejuni infections constitute serious threats to human health with increasing prevalences worldwide. Our knowledge regarding the molecular mechanisms underlying host–pathogen interactions is still limited. Our group has established a clinical C. jejuni infection model based on abiotic IL-10 −/− mice mimicking key features of human campylobacteriosis. In order to further validate this model for unraveling pathogen-host interactions mounting in acute disease, we here surveyed the immunopathological features of the important C. jejuni virulence factors FlaA and FlaB and the major adhesin CadF ( Campylobacter adhesin to fibronectin), which play a role in bacterial motility, protein secretion and adhesion, respectively. Methods and results Therefore, abiotic IL-10 −/− mice were perorally infected with C. jejuni strain 81-176 (WT) or with its isogenic flaA/B (Δ flaA/B ) or cadF (Δ cadF ) deletion mutants. Cultural analyses revealed that WT and Δ cadF but not Δ flaA/B bacteria stably colonized the stomach, duodenum and ileum, whereas all three strains were present in the colon at comparably high loads on day 6 post-infection. Remarkably, despite high colonic colonization densities, murine infection with the Δ flaA/B strain did not result in overt campylobacteriosis, whereas mice infected with Δ cadF or WT were suffering from acute enterocolitis at day 6 post-infection. These symptoms coincided with pronounced pro-inflammatory immune responses, not only in the intestinal tract, but also in other organs such as the liver and kidneys and were accompanied with systemic inflammatory responses as indicated by increased serum MCP-1 concentrations following C. jejuni Δ cadF or WT, but not Δ flaA/B strain infection. Conclusion For the first time, our observations revealed that the C. jejuni flagellins A/B, but not adhesion mediated by CadF, are essential for inducing murine campylobacteriosis. Furthermore, the secondary abiotic IL-10 −/− infection model has been proven suitable not only for detailed investigations of immunological aspects of campylobacteriosis, but also for differential analyses of the roles of distinct C. jejuni virulence factors in induction and progression of disease. Electronic supplementary material The online version of this article (10.1186/s13099-019-0306-9) contains supplementary material, which is available to authorized users. ...

Foes or Friends? Bacteria Enriched in the Tumor Microenvironment of Colorectal Cancer

“…The colonization of C. jejuni in the intestine is mediated by the binding of Campylobacter adhesin to fibronectin (CadF), fibronectin-like protein (FlpA), and permease PEB1 with their corresponding targets (Table 4). Both CadF and FlpA can bind to fibronectin, which is the main ingredient of the extracellular matrix of intestinal epithelial cells, leading to the colonization of C. jejuni in the intestine [53,54]. The colonization mechanism mediated by PEB1 is unclear, but the colonization capacity of PEB1-deleted strains is found to reduce by 50-100 folds [55].…”

Novel Clinical Campylobacter jejuni Infection Models Based on Sensitization of Mice to Lipooligosaccharide, a Major Bacterial Factor Triggering Innate Immune Responses in Human Campylobacteriosis

“…In particular, the LOS sensitized secondary abiotic IL-10 deficient mice were successfully used for groundbreaking studies for a better molecular understanding of immunopathogenesis of campylobacteriosis. In this model, murine symptoms mimic human disease and induction of intestinal inflammation strictly depends on the motility and invasive properties of C. jejuni [28]. It is of note that commensal E. coli lacking any invasive or other pathogenic properties do not induce pathology in this model [50].…”

“…Similar to the vast majority of bacterial enteric pathogens causing inflammatory diseases in the gastrointestinal tract, C. jejuni enters the gut via ingestion of food contaminated with a low number of live bacteria [26]. After replication at body temperature and establishment of a primary population, the highly motile C. jejuni pass the barriers of the viscous mucus layer (Figure 1) and the epithelial cell lining with the help of polar flagella, adhesins, and invasins including potent proteases such as HtrA further supporting transcellular migration of the bacteria [27][28][29][30]. Most recently, the type VI secretion system (T6SS) of C. jejuni was discovered as a factor which might be involved in virulence.…”

“…The isolation of C. jejuni from mesenteric lymph nodes (MLNs), liver, kidneys, spleen and cardiac blood indicated that invading bacteria had been able to translocate from the inflamed intestines to extra-intestinal and even systemic compartments, further perpetuating the fatal inflammatory scenario. Overall, the secondary abiotic IL-10 −/− mouse model has been proven valuable to unravelling the immunopathological impact of distinct C. jejuni virulence factor involved in human disease [28,43,47,48,52,64].…”

Molecular Dissection of the Campylobacter jejuni CadF and FlpA Virulence Proteins in Binding to Host Cell Fibronectin

“…In a recent study, the contribution of the CadF adhesin to disease was assessed by infecting abiotic (gnotobiotic) IL-10 −/− mice with the C. jejuni 81-176 wild-type strain and with a cadF deletion mutant [65]. In this model, the animals were inoculated with C. jejuni (10 9 CFU on two consecutive days), and disease parameters were assessed daily until six days post-infection.…”