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IFN-g counteracts YopH mediated immune evasion in Yersinia enterocolitica infection in mice

ABSTRACT: Background: Yersinia outer protein (Yop) H is a secreted virulence factor of Yersinia enterocolitica which inhibits phagocytosis of Y. enterocolitica and promotes virulence of Y. enterocolitica (Ye) in mice. The aim of this study was to address whether and how YopH affects the innate immune response against Ye in mice. Results: For this purpose mice were infected with wild type Ye (pYV+) or a YopH-deficient Ye mutant strain (DyopH). CD11b+ cells were isolated from infected spleen and subjected to gene expression analysis using microarrays. Despite attenuation of DyopH in vivo, by variation of infection doses we were able to achieve conditions that allow comparison of gene expression in pYV+ and DyopH infections at either comparable infection courses or splenic bacterial burden. Gene expression analysis provided evidence that expression levels of several immune response genes including IFN-g and IL-6 are high after pYV+ infection but low after sublethal DyopH infection. In line with these findings, infection of IFN-gR-/- and IL-6-/- mice with pYV+ or DyopH revealed that these cytokines are dispensable for control of DyopH, but not pYV+ infection. Consistently, in bacteria killing assays with BMM in vitro, stimulation of BMM with IFN-g is required for killing of pYV+ but not DyopH. Conclusion: In conclusion, this data suggest that IFN-g counteracts YopH-mediated virulence mechanisms of Ye which in Ye wild type infection contribute to evasion of the innate immune response including killing by macrophages. Keywords: Comparison of gene expression due to bacterial virulence factors

ORGANISM(S): Mus musculus

PROVIDER: GSE11189 | GEO | 2008/04/17

SECONDARY ACCESSION(S): PRJNA106895

REPOSITORIES: GEO

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Project description:Background:; Yersinia outer protein (Yop) H is a secreted virulence factor of Yersinia enterocolitica which inhibits phagocytosis of Y. enterocolitica and promotes virulence of Y. enterocolitica (Ye) in mice. The aim of this study was to address whether and how YopH affects the innate immune response against Ye in mice. Results:; For this purpose mice were infected with wild type Ye (pYV+) or a YopH-deficient Ye mutant strain (DyopH). CD11b+ cells were isolated from infected spleen and subjected to gene expression analysis using microarrays. Despite attenuation of DyopH in vivo, by variation of infection doses we were able to achieve conditions that allow comparison of gene expression in pYV+ and DyopH infections at either comparable infection courses or splenic bacterial burden. Gene expression analysis provided evidence that expression levels of several immune response genes including IFN-g and IL-6 are high after pYV+ infection but low after sublethal DyopH infection. In line with these findings, infection of IFN-gR-/- and IL-6-/- mice with pYV+ or DyopH revealed that these cytokines are dispensable for control of DyopH, but not pYV+ infection. Consistently, in bacteria killing assays with BMM in vitro, stimulation of BMM with IFN-g is required for killing of pYV+ but not DyopH. Conclusion:; In conclusion, this data suggest that IFN-g counteracts YopH-mediated virulence mechanisms of Ye which in Ye wild type infection contribute to evasion of the innate immune response including killing by macrophages. Experiment Overall Design: In this study microarray analyses were performed to define differences in gene expression of cells associated with innate immune response (CD11b+ cells) after infection of mice with a sublethal and lethal infection with wildtype Yersinia enterocolitica compared to uninfected mice. In addition, we wanted to investigate whether differences in gene expression can be defined which are due to the virulence factor YopH. Moroeover, we were interested whether gene expression pattern of sublethal and lethal infected mice are different. Allover all five samples were compared. Number of replicates 1.

Project description:ABSTRACT Macrophages are essential components of the innate immune system and crucial for pathogen elimination in early stages of infection. We previously observed that bone marrow-derived macrophages (BMM) from C57BL/6 mice exhibited increased killing activity against Burkholderia pseudomallei compared to BMM from BALB/c mice. This effect was particularly pronounced when cells were treated with IFN-M-NM-3. To unravel mechanisms that could explain these distinct bactericidal effects, a comparative combined proteome and transcriptome analysis of untreated and IFN-M-NM-3 treated BALB/c and C57BL/6 BMM under standardized serum-free conditions was carried out. We found differences in gene expression/ protein abundance belonging to cellular oxidative and antioxidative stress systems. Genes/ proteins involved in the generation of oxidant molecules and the function of phagosomes (respiratory chain ATPase, lysosomal enzymes, cathepsin) were predominantly higher expressed/ more abundant in C57BL/6 BMM. Components involved in alleviation of oxidative stress (peroxiredoxin, mitochondrial superoxide dismutase) were more abundant in C57BL/6 BMM as well. Thus, C57BL/6 BMM seemed to be better equipped with cellular systems that may be advantageous in combating engulfed pathogens. Simultaneously, C57BL/6 BMM were well protected from oxidative burst. We assume that these variations co-determine differences in resistance between BALB/c and C57BL/6 mice observed in many infection models. Biological significance: In this study we performed combined transcriptome and proteome analyses on BMM derived from two inbred mouse strains that are frequently used for studies in the field of host-pathogen interaction research. Strain differences between BALB/c and C57BL/6 BMM were found to originate mainly from different protein abundance levels rather than from different gene expression. Differences in abundance of respiratory chain complexes and phagosomal proteins as well as differential regulation of components belonging to various antioxidant stress systems help to explain long-known differences between the mouse strains concerning their different susceptibility in several infection models. In this study 12 samples were analyzed. They are classified into four groups: BMM of Balb/c mice medium control, BMM of Balb/c mice interferon gamma treated, BMM of C57Bl/6 mice medium control, and BMM of C57Bl/6 mice interferon gamma treated. Each of the four groups contains 3 biological replicates.

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IFN-g counteracts YopH mediated immune evasion in Yersinia enterocolitica infection in mice

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