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YopJ-promoted cytotoxicity and systemic colonization are associated with high levels of murine interleukin-18, gamma interferon, and neutrophils in a live vaccine model of Yersinia pseudotuberculosis infection.

ABSTRACT: Several Yersinia species have been utilized as live attenuated vaccines to prime protective immunity against yersiniae and other pathogens. A type III secretion system effector known as YopJ in Y. pseudotuberculosis and Y. pestis and YopP in Y. enterocolitica has been shown to regulate host immune responses to live Yersinia vaccines. YopJ/P kills macrophages and dendritic cells, reduces their production of tumor necrosis factor alpha (TNF-alpha) and interleukin-12 (IL-12), and promotes systemic colonization in mouse models of intestinal Yersinia infection. Furthermore, YopP activity decreases antigen presentation by dendritic cells, and a yopP mutant of a live Y. enterocolitica carrier vaccine elicited effective priming of CD8 T cells to a heterologous antigen in mice. These results suggest that YopJ/P activity suppresses both innate and adaptive immune responses to live Yersinia vaccines. Here, a sublethal intragastric mouse infection model using wild-type and catalytically inactive yopJ mutant strains of Y. pseudotuberculosis was developed to further investigate how YopJ action impacts innate and adaptive immune responses to a live vaccine. Surprisingly, YopJ-promoted cytotoxicity and systemic colonization were associated with significant increases in neutrophils in spleens and the proinflammatory cytokines IL-18 and gamma interferon (IFN-gamma) in serum samples of mice vaccinated with Y. pseudotuberculosis. Secretion of IL-18 accompanied YopJ-mediated killing of macrophages infected ex vivo with Y. pseudotuberculosis, suggesting a mechanism by which this effector directly increases proinflammatory cytokine levels in vivo. Mice vaccinated with the wild-type strain or the yopJ mutant produced similar levels of antibodies to Y. pseudotuberculosis antigens and were equally resistant to lethal intravenous challenge with Y. pestis. The findings indicate that a proinflammatory, rather than anti-inflammatory, process accompanies YopJ-promoted cytotoxicity, leading to increased systemic colonization by Y. pseudotuberculosis and potentially enhancing adaptive immunity to a live vaccine.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC2863517 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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YopJ-promoted cytotoxicity and systemic colonization are associated with high levels of murine interleukin-18, gamma interferon, and neutrophils in a live vaccine model of Yersinia pseudotuberculosis infection.

Zhang Yue Y Bliska James B JB

Infection and immunity 20100315 5

Several Yersinia species have been utilized as live attenuated vaccines to prime protective immunity against yersiniae and other pathogens. A type III secretion system effector known as YopJ in Y. pseudotuberculosis and Y. pestis and YopP in Y. enterocolitica has been shown to regulate host immune responses to live Yersinia vaccines. YopJ/P kills macrophages and dendritic cells, reduces their production of tumor necrosis factor alpha (TNF-alpha) and interleukin-12 (IL-12), and promotes systemic ...[more]

PMID: 20231414

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Project description:Prostaglandin E2 (PGE2) is an essential immunomodulatory lipid released by cells in response to infection with many bacteria, yet its function in macrophage-mediated bacterial clearance is poorly understood. Yersinia overall inhibits the inflammatory circuit, but its effect on PGE2 production is unknown. We hypothesized that one of the Yersinia effector proteins is responsible for the inhibition of PGE2 biosynthesis. We identified that yopB-deficient Y. enterocolitica and Y. pseudotuberculosis deficient in the secretion of virulence proteins via a type 3 secretion system (T3SS) failed to inhibit PGE2 biosynthesis in macrophages. Consistently, COX-2-mediated PGE2 biosynthesis is upregulated in cells treated with heat-killed or T3SS-deficient Y. pseudotuberculosis but diminished in the presence of a MAPK/ERK inhibitor. Mutants expressing catalytically inactive YopJ induce similar levels of PGE2 as heat-killed or ΔyopB Y. pseudotuberculosis, reversed by YopJ complementation. Shotgun proteomics discovered host pathways regulated in a YopJ-mediated manner, including pathways regulating PGE2 synthesis and oxidative phosphorylation. Consequently, this study identified that YopJ-mediated inhibition of MAPK signal transduction serves as a mechanism targeting PGE2, an alternative means of inflammasome inhibition by Yersinia. Finally, we showed that EP4 signaling supports macrophage function in clearing intracellular bacteria. In summary, our unique contribution was to determine a bacterial virulence factor that targets COX-2 transcription, thereby enhancing the intracellular survival of yersiniae. Future studies should investigate whether PGE2 or its stable synthetic derivatives could serve as a potential therapeutic molecule to improve the outcomes of specific bacterial infections. Since other pathogens encode YopJ homologs, this mechanism is expected to be present in other infections. IMPORTANCE PGE2 is a critical immunomodulatory lipid, but its role in bacterial infection and pathogen clearance is poorly understood. We previously demonstrated that PGE2 leads to macrophage polarization toward the M1 phenotype and stimulates inflammasome activation in infected macrophages. Finally, we also discovered that PGE2 improved the clearance of Y. enterocolitica. The fact that Y. enterocolitica hampers PGE2 secretion in a type 3 secretion system (T3SS)-dependent manner and because PGE2 appears to assist macrophage in the clearance of this bacterium indicates that targeting of the eicosanoid pathway by Yersinia might be an adaption used to counteract host defenses. Our study identified a mechanism used by Yersinia that obstructs PGE2 biosynthesis in human macrophages. We showed that Y. pseudotuberculosis interferes with PGE2 biosynthesis by using one of its T3SS effectors, YopJ. Specifically, YopJ targets the host COX-2 enzyme responsible for PGE2 biosynthesis, which happens in a MAPK/ER-dependent manner. Moreover, in a shotgun proteomics study, we also discovered other pathways that catalytically active YopJ targets in the infected macrophages. YopJ was revealed to play a role in limiting host LPS responses, including repression of EGR1 and JUN proteins, which control transcriptional activation of proinflammatory cytokine production such as interleukin-1β. Since YopJ has homologs in other bacterial species, there are likely other pathogens that target and inhibit PGE2 biosynthesis. In summary, our study's unique contribution was to determine a bacterial virulence factor that targets COX-2 transcription. Future studies should investigate whether PGE2 or its stable synthetic derivatives could serve as a potential therapeutic target.

Dataset Information

YopJ-promoted cytotoxicity and systemic colonization are associated with high levels of murine interleukin-18, gamma interferon, and neutrophils in a live vaccine model of Yersinia pseudotuberculosis infection.

Publications

YopJ-promoted cytotoxicity and systemic colonization are associated with high levels of murine interleukin-18, gamma interferon, and neutrophils in a live vaccine model of Yersinia pseudotuberculosis infection.

Similar Datasets

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