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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: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.

Similar Datasets

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