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Exposure of Campylobacter jejuni to acid stress enhances its pathogenesis and cross-protects the bacterium against other stresses

ABSTRACT: Campylobacter jejuni is the prevalent cause of bacterial gastroenteritis in human worldwide. The ability to survive stomach acidity is a fundamental requirement for C. jejuni to colonize the host and cause disease. However, the mechanism of C. jejuni acid survival is still unknown. Herein, we demonstrated that C. jejuni is able to survive acidic conditions at pH 4 up to 8 min without a drop in viability. The acid stimulon of C. jejuni 81-176 revealed the up-regulation of many genes important for Campylobacter acid survival such as heat shock genes and genes involved in energy metabolism. On the other hand, the repression of ribosomal genes highlights the ability of C. jejuni to direct its machinery to survive stressful conditions. Prior acid exposure cross-protected C. jejuni against oxidative stress suggesting an overlap in C. jejuni’s responses to various stresses. Interestingly, the induced expression of virulence genes in C. jejuni upon acid exposure such as the Campylobacter invasion antigen (ciaB) indicates that acid stress plays a role in C. jejuni host pathogenesis. Acid exposure significantly enhanced C. jejuni pathogenesis in both eukaryotic cells and G. melonella. To the best of our knowledge, this is the first study characterizes the influence of acid stress on C. jejuni pathogenesis in an infection model. Altogether, this study uncovers the transcriptional profile of C. jejuni in response to acidic conditions as those encountered in the stomach. In addition, our results demonstrate that acid stress jump-starts C. jejuni for efficient gut colonization and host pathogenesis. Campylobacter jejuni is the prevalent cause of bacterial gastroenteritis in human worldwide. The ability to survive stomach acidity is a fundamental requirement for C. jejuni to colonize the host and cause disease. However, the mechanism of C. jejuni acid survival is still unknown. Herein, we demonstrated that C. jejuni is able to survive acidic conditions at pH 4 up to 8 min without a drop in viability. The acid stimulon of C. jejuni 81-176 revealed the up-regulation of many genes important for Campylobacter acid survival such as heat shock genes and genes involved in energy metabolism. On the other hand, the repression of ribosomal genes highlights the ability of C. jejuni to direct its machinery to survive stressful conditions. Prior acid exposure cross-protected C. jejuni against oxidative stress suggesting an overlap in C. jejuni’s responses to various stresses. Interestingly, the induced expression of virulence genes in C. jejuni upon acid exposure such as the Campylobacter invasion antigen (ciaB) indicates that acid stress plays a role in C. jejuni host pathogenesis. Acid exposure significantly enhanced C. jejuni pathogenesis in both eukaryotic cells and G. melonella. To the best of our knowledge, this is the first study characterizes the influence of acid stress on C. jejuni pathogenesis in an infection model. Altogether, this study uncovers the transcriptional profile of C. jejuni in response to acidic conditions as those encountered in the stomach. In addition, our results demonstrate that acid stress jump-starts C. jejuni for efficient gut colonization and host pathogenesis.

ORGANISM(S): Campylobacter jejuni

PROVIDER: GSE73793 | GEO | 2016/10/01

SECONDARY ACCESSION(S): PRJNA297900

REPOSITORIES: GEO

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Project description:Campylobacter jejuni is a prevalent cause of bacterial gastroenteritis in humans worldwide. The mechanism by which C. jejuni survives stomach acidity remains unknown. Herein, we have demonstrated that C. jejuni with a fur deletion was more sensitive to acid than the wild-type strain. Profiling the acid stimulon of the C. jejuni ∆fur mutant allowed us to uncover Fur-regulated genes under acidic conditions. The up-regulation of heat shock genes and the down-regulation of genes involved in flagellar and cell envelope biogenesis in the fur mutant highlight the importance of Fur in Campylobacter acid survival. Interestingly, prior acid exposure of C. jejuni cross-protected the bacterium against oxidative stress. Western-blot analysis and real-time qRT-PCR revealed an increased expression of the catalase KatA in acid-stressed C. jejuni relative to unstressed bacteria. The enhanced survival of C. jejuni to oxidative stress was shown to be Fur-dependent through the regulation of katA expression. Electrophoretic mobility shift assay (EMSA) demonstrated that the binding affinity between Fur and katA is reduced under low pH allowing for higher expression of katA and the defense against oxidative stress. Strikingly, the ∆fur mutant exhibited a reduced virulence capacity in both human epithelial cells and G. mellonella infection model as compared to C. jejuni wild-type. Altogether, this is the first study showing that in addition to its role in iron metabolism, Fur is an important regulator of C. jejuni acid response and cross-protection against other stresses. Moreover, our results clearly demonstrate that Fur plays a substantial role in C. jejuni host pathogenesis. Campylobacter jejuni is a prevalent cause of bacterial gastroenteritis in humans worldwide. The mechanism by which C. jejuni survives stomach acidity remains unknown. Herein, we have demonstrated that C. jejuni with a fur deletion was more sensitive to acid than the wild-type strain. Profiling the acid stimulon of the C. jejuni ∆fur mutant allowed us to uncover Fur-regulated genes under acidic conditions. The up-regulation of heat shock genes and the down-regulation of genes involved in flagellar and cell envelope biogenesis in the fur mutant highlight the importance of Fur in Campylobacter acid survival. Interestingly, prior acid exposure of C. jejuni cross-protected the bacterium against oxidative stress. Western-blot analysis and real-time qRT-PCR revealed an increased expression of the catalase KatA in acid-stressed C. jejuni relative to unstressed bacteria. The enhanced survival of C. jejuni to oxidative stress was shown to be Fur-dependent through the regulation of katA expression. Electrophoretic mobility shift assay (EMSA) demonstrated that the binding affinity between Fur and katA is reduced under low pH allowing for higher expression of katA and the defense against oxidative stress. Strikingly, the ∆fur mutant exhibited a reduced virulence capacity in both human epithelial cells and G. mellonella infection model as compared to C. jejuni wild-type. Altogether, this is the first study showing that in addition to its role in iron metabolism, Fur is an important regulator of C. jejuni acid response and cross-protection against other stresses. Moreover, our results clearly demonstrate that Fur plays a substantial role in C. jejuni host pathogenesis.

Project description:Background: The food-borne pathogen Campylobacter is one of the most important zoonotic pathogens. Compared to other zoonotic bacteria, Campylobacter species are quite susceptible to environmental or technological stressors. This might be due to the lack of many stress response mechanisms described in other bacteria. Nevertheless, Campylobacter is able to survive in the environment and food products. Although some aspects of the heat stress response in Campylobacter (C.) jejuni are already known, information about the heat stress response in the related species C. coli and C. lari are still unknown. Results: The stress response to elevated temperatures (46°C) was investigated by survival assays and whole transcriptome analyses for the strain C. jejuni NCTC11168, C. coli RM2228 and C. lari RM2100. While C. jejuni showed highest thermotolerance followed by C. lari and C. coli, none of the strains survived at this temperature for more than 24 hours. Transcriptomic analyses revealed that only 3 % of the genes in C. jejuni and approx. 20 % of the genes of C. coli and C. lari were differentially expressed after heat stress, respectively. The transcriptomic profiles showed enhanced gene expression of several chaperones like dnaK, groES, groEL and clpB in all strains, but differences in the gene expression of transcriptional regulators like hspR, perR as well as for genes involved in metabolic pathways, translation processes and membrane components. However, the function of many of the differentially expressed gene is unknown so far. Conclusion: We could demonstrate differences in the ability to survive at elevated temperatures for C. jejuni, C. coli and C. lari and showed for the first time transcriptomic analyses of the heat stress response of C. coli and C. lari. Our data suggest that the heat stress response of C. coli and C. lari are more similar to each other compared to C. jejuni, even though on genetic level a higher homology exists between C. jejuni and C. coli. This indicates that stress response mechanisms described for C. jejuni might be unique for this species and not necessarily transferable to other Campylobacter species.

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Exposure of Campylobacter jejuni to acid stress enhances its pathogenesis and cross-protects the bacterium against other stresses

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