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Phosphatidylinositol 3-kinase-? signaling promotes Campylobacter jejuni-induced colitis through neutrophil recruitment in mice.

ABSTRACT: Crypt abscesses caused by excessive neutrophil accumulation are prominent features of human campylobacteriosis and its associated pathology. The molecular and cellular events responsible for this pathological situation are currently unknown. We investigated the contribution of PI3K-? signaling in Campylobacter jejuni-induced neutrophil accumulation and intestinal inflammation. Germ-free and specific pathogen-free Il10(-/-) and germ-free Il10(-/-);Rag2(-/-) mice were infected with C. jejuni (10(9) CFU/mouse). PI3K-? signaling was manipulated using either the pharmacological PI3K-? inhibitor AS252424 (i.p. 10 mg/kg daily) or genetically using Pi3k-?(-/-) mice. After up to 14 d, inflammation was assessed histologically and by measuring levels of colonic Il1?, Cxcl2, and Il17a mRNA. Neutrophils were depleted using anti-Gr1 Ab (i.p. 0.5 mg/mouse/every 3 d). Using germ-free Il10(-/-);Rag2(-/-) mice, we observed that innate immune cells are the main cellular compartment responsible for campylobacteriosis. Pharmacological blockade of PI3K-? signaling diminished C. jejuni-induced intestinal inflammation, neutrophil accumulation, and NF-?B activity, which correlated with reduced Il1? (77%), Cxcl2 (73%), and Il17a (72%) mRNA accumulation. Moreover, Pi3k-?(-/-) mice pretreated with anti-IL-10R were resistant to C. jejuni-induced intestinal inflammation compared with Wt mice. This improvement was accompanied by a reduction of C. jejuni translocation into the colon and extraintestinal tissues and by attenuation of neutrophil migratory capacity. Furthermore, neutrophil depletion attenuated C. jejuni-induced crypt abscesses and intestinal inflammation. Our findings indicate that C. jejuni-induced PI3K-? signaling mediates neutrophil recruitment and intestinal inflammation in Il10(-/-) mice. Selective pharmacological inhibition of PI3K-? may represent a novel means to alleviate severe cases of campylobacteriosis, especially in antibiotic-resistant strains.

SUBMITTER: Sun X

PROVIDER: S-EPMC3529774 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Phosphatidylinositol 3-kinase-γ signaling promotes Campylobacter jejuni-induced colitis through neutrophil recruitment in mice.

Sun Xiaolun X Liu Bo B Sartor Ryan Balfour RB Jobin Christian C

Journal of immunology (Baltimore, Md. : 1950) 20121123 1

Crypt abscesses caused by excessive neutrophil accumulation are prominent features of human campylobacteriosis and its associated pathology. The molecular and cellular events responsible for this pathological situation are currently unknown. We investigated the contribution of PI3K-γ signaling in Campylobacter jejuni-induced neutrophil accumulation and intestinal inflammation. Germ-free and specific pathogen-free Il10(-/-) and germ-free Il10(-/-);Rag2(-/-) mice were infected with C. jejuni (10(9 ...[more]

PMID: 23180818

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Project description:Globally, Campylobacter spp. are the most common food-associated bacterial cause of human gastrointestinal disease. Campylobacteriosis is primarily associated with the consumption of contaminated chicken meat. Chemical decontamination of chicken carcasses during processing is one of the most effective interventions to mitigate Campylobacter contamination. Following exposure to sanitizers, however, sublethally injured populations of bacteria may persist. The risk that sublethally injured Campylobacter pose for public health is unknown. Furthermore, the virulence potential of sublethally injured Campylobacter jejuni during prolonged storage in relation to host pathogenesis and the host immune response has not been well established. Therefore, we evaluated the effects of sublethally injured C. jejuni on the host, after storage in chicken meat juice. C57BL/6 mice were infected with two C. jejuni chicken meat isolates or the ATCC 33291 strain that had been stored in the chicken meat juice, after exposure to chlorine or acidified sodium chlorite (ASC). Although chlorine exposure was unable to reduce intestinal colonization by C. jejuni, exposure to ASC significantly reduced the intestinal colonization and tissue translocation in mice. The expression of pro- and anti-inflammatory cytokine genes for interleukin-6 (IL-6), IL23a, and IL-10, Toll-like receptor 2 (TLR2) and TLR4 genes, and host stress response genes (CRP, MBL1, and NF-κB1) were significantly reduced following the exposure to ASC. Our results demonstrated that sublethally injured C. jejuni has reduced virulence potential and colonization in mice. The data contribute toward clarification of the importance of chemical decontamination during processing to minimize human campylobacteriosis. IMPORTANCE Campylobacter is the most common cause of bacterial gastrointestinal disease, and consumption of contaminated poultry is frequently identified as the source of bacteria. The survivability and virulence potential of sublethally injured Campylobacter following exposure to chemicals which are commonly used to eliminate Campylobacter during the poultry meat processing are of concern to the food industry, government health officials, and consumers. Here, we demonstrate that sublethally injured Campylobacter jejuni has reduced bacterial virulence and colonization potential in mice.

Project description:Campylobacter jejuni is the leading cause of bacterial gastroenteritis in the developed world. Despite its prevalence, relatively little is known about C. jejuni's precise pathogenesis mechanisms, particularly in comparison to other well-studied enteric organisms such as Escherichia coli and Salmonella spp. Altered expression of phosphate genes in a C. jejuni stringent response mutant, together with known correlations between the stringent response, polyphosphate (poly-P), and virulence in other bacteria, led us to investigate the role of poly-P in C. jejuni stress survival and pathogenesis. All sequenced C. jejuni strains harbor a conserved putative polyphosphate kinase 1 predicted to be principally responsible for poly-P synthesis. We generated a targeted ppk1 deletion mutant (Deltappk1) in C. jejuni strain 81-176 and found that Deltappk1, as well as the DeltaspoT stringent response mutant, exhibited low levels of poly-P at all growth stages. In contrast, wild-type C. jejuni poly-P levels increased significantly as the bacteria transitioned from log to stationary phase. Phenotypic analyses revealed that the Deltappk1 mutant was defective for survival during osmotic shock and low-nutrient stress. However, certain phenotypes associated with ppk1 deletion in other bacteria (i.e., motility and oxidative stress) were unaffected in the C. jejuni Deltappk1 mutant, which also displayed an unexpected increase in biofilm formation. The C. jejuni Deltappk1 mutant was also defective for the virulence-associated phenotype of intraepithelial cell survival in a tissue culture infection model and exhibited a striking, dose-dependent chick colonization defect. These results indicate that poly-P utilization and accumulation contribute significantly to C. jejuni pathogenesis and affect its ability to adapt to specific stresses and stringencies. Furthermore, our study demonstrates that poly-P likely plays both similar and unique roles in C. jejuni compared to its roles in other bacteria and that poly-P metabolism is linked to stringent response mechanisms in C. jejuni.

Dataset Information

Phosphatidylinositol 3-kinase-? signaling promotes Campylobacter jejuni-induced colitis through neutrophil recruitment in mice.

Publications

Phosphatidylinositol 3-kinase-γ signaling promotes Campylobacter jejuni-induced colitis through neutrophil recruitment in mice.

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