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Edwardsiella tarda-Induced Inhibition of Apoptosis: A Strategy for Intracellular Survival.

ABSTRACT: Edwardsiella tarda is a Gram-negative bacterial pathogen that can infect a wide range of freshwater and marine fish. One salient feature of E. tarda is the ability to survive and replicate in various host cells. In this study, we observed that E. tarda replicated robustly in the zebrafish cell line ZF4, and that E. tarda-infected cells exhibited no detectable signs of apoptosis. Global transcriptome analysis and quantitative real-time RT-PCR revealed that E. tarda infection generally significantly downregulated pro-apoptotic genes and upregulated anti-apoptotic genes. To investigate the role of apoptosis in E. tarda infection, two upregulated anti-apoptotic genes (Fech and Prx3) and two downregulated pro-apoptotic genes (Brms1a and Ivns1a) were overexpressed in zebrafish. Subsequent infection study showed that Fech and Prx3 overexpression significantly promoted E. tarda dissemination in and colonization of fish tissues, while Brms1a and Ivns1a overexpression significantly reduced E. tarda dissemination and colonization. Consistently, when Fech and Prx3 were knocked down in zebrafish, E. tarda infection was significantly inhibited, whereas Brms1a and Ivns1a knockdown significantly enhanced E. tarda infection. These results indicate for the first time that E. tarda prevents apoptosis in teleost as a strategy for intracellular survival, and that some putative apoptotic genes of teleost function in the apoptosis pathway probably in a manner similar to that in mammalian systems.

SUBMITTER: Zhou ZJ

PROVIDER: S-EPMC4943942 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Edwardsiella tarda-Induced Inhibition of Apoptosis: A Strategy for Intracellular Survival.

Zhou Ze-Jun ZJ Sun Li L

Frontiers in cellular and infection microbiology 20160714

Edwardsiella tarda is a Gram-negative bacterial pathogen that can infect a wide range of freshwater and marine fish. One salient feature of E. tarda is the ability to survive and replicate in various host cells. In this study, we observed that E. tarda replicated robustly in the zebrafish cell line ZF4, and that E. tarda-infected cells exhibited no detectable signs of apoptosis. Global transcriptome analysis and quantitative real-time RT-PCR revealed that E. tarda infection generally significant ...[more]

PMID: 27471679

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Project description:Edwardsiella tarda is a severe fish pathogen, featured by its capacity to live inside host phagocytes. For intracellular survival, it is crucial for E. tarda to neutralize the deleterious effect of host reactive oxygen species (ROS). Accumulating evidence suggests that bacterial metabolism is closely connected to oxidative resistance. However, the roles of E. tarda metabolic proteins in antioxidative adaptation and intracellular proliferation remain elusive. In this study, we performed a proteomic analysis on E. tarda and identified 111 proteins responsive to H2O2-mediated oxidative stress. Based on this data, we further obtained eight crucial proteins, including seven metabolic proteins, for E. tarda antioxidation and intracellular infection. Among them, two C4-dicarboxylate transporters were found necessary for E. tarda to disseminate in fish tissues. Furthermore, the substrate of the two transporters was identified as L-aspartate, which was proven to be essential for the full antioxidative capacity of E. tarda. Our results indicate that reprogramming the metabolic flux to the production of pyruvate, a ketoacid capable of neutralizing ROS, was likely a pivotal strategy of E. tarda to survive the oxidative environments inside host cells. Together, the findings of this study highlight the significance of metabolic reprogramming for bacterial redox homeostasis and intracellular infection. IMPORTANCE Edwardsiella tarda is a significant fish pathogen that can live in challenging environments of reactive oxygen species (ROS), such as inside the phagocytes. Metabolic reconfiguration has been increasingly associated with bacterial oxidative tolerance and virulence. However, the metabolic proteins of E. tarda involved in such processes remain elusive. By proteomic analysis and functional characterization of protein null mutants, the present study identified eight crucial proteins for bacterial oxidative resistance and intracellular infection. Seven of them are metabolic proteins dictating the metabolic flux toward the generation of pyruvate, a key metabolite capable of scavenging ROS molecules. Furthermore, L-aspartate uptake, which can fuel the pyruvate generation, was found essential for the full antioxidative capacity of E. tarda. These findings identified seven metabolic proteins involved in bacterial oxidative adaptation and indicate that metabolic reprogramming toward pyruvate was likely a pivotal strategy of bacteria for antioxidative adaptation and intracellular survival.

Project description:UnlabelledEdwardsiella tarda is an important pathogenic bacterium that can replicate in macrophages. However, how the intramacrophage infection process affects the virulence of this bacterium is essentially unknown. Here, we show that E. tarda replicates and induces a caspase-1-dependent cell pyroptosis in a murine macrophage model. Via pyroptosis, intracellular E. tarda escapes to the extracellular milieu, forming a unique bacterial population. Being different from the bacteria cultured alone, this unique population possesses a reprogrammed transcriptional profile, particularly with upregulated type III secretion system (T3SS)/T6SS cluster genes. Subsequent studies revealed that the macrophage-released population gains enhanced infectivity for host epithelial cells and increases resistance to multiple host defenses and hence displays significantly promoted virulence in vivo Further studies indicated that T3SS is essentially required for the macrophage infection process, while T6SS contributes to infection-induced bacterial virulence. Altogether, this work demonstrates that E. tarda can utilize macrophages as a niche for virulence priming and for spreading infection, suggesting a positive role for intramacrophage infection in bacterial pathogenesis.ImportanceMany pathogens can replicate in macrophages, which is crucial for their pathogenesis. To survive in the macrophage cell, pathogens are likely to require fitness genes to counteract multiple host-killing mechanisms. Here, Edwardsiella tarda is proved to exit from macrophages during infection. This macrophage-released population displays a reprogrammed transcriptional profile with significantly upregulated type III secretion system (T3SS)/T6SS-related genes. Furthermore, both enhanced infectivity in epithelial cells and activated resistance to complex host defenses were conferred on this macrophage-primed population, which consequently promoted the full virulence of E. tarda in vivo Our work provides evidence that E. tarda can utilize macrophages as a niche for virulence priming and for spreading infection, highlighting the importance of the intramacrophage infection cycle for the pathogenesis of E. tarda.

Dataset Information

Edwardsiella tarda-Induced Inhibition of Apoptosis: A Strategy for Intracellular Survival.

Publications

Edwardsiella tarda-Induced Inhibition of Apoptosis: A Strategy for Intracellular Survival.

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