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Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection.

ABSTRACT: Salmonella Typhi activates the host DNA damage response through the typhoid toxin, facilitating typhoid symptoms and chronic infections. Here we reveal a non-canonical DNA damage response, which we call RING (response induced by a genotoxin), characterized by accumulation of phosphorylated histone H2AX (?H2AX) at the nuclear periphery. RING is the result of persistent DNA damage mediated by toxin nuclease activity and is characterized by hyperphosphorylation of RPA, a sensor of single-stranded DNA (ssDNA) and DNA replication stress. The toxin overloads the RPA pathway with ssDNA substrate, causing RPA exhaustion and senescence. Senescence is also induced by canonical ??2?? foci revealing distinct mechanisms. Senescence is transmitted to non-intoxicated bystander cells by an unidentified senescence-associated secreted factor that enhances Salmonella infections. Thus, our work uncovers a mechanism by which genotoxic Salmonella exhausts the RPA response by inducing ssDNA formation, driving host cell senescence and facilitating infection.

SUBMITTER: Ibler AEM

PROVIDER: S-EPMC6731267 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection.

Ibler Angela E M AEM ElGhazaly Mohamed M Naylor Kathryn L KL Bulgakova Natalia A NA F El-Khamisy Sherif S Humphreys Daniel D

Nature communications 20190906 1

Salmonella Typhi activates the host DNA damage response through the typhoid toxin, facilitating typhoid symptoms and chronic infections. Here we reveal a non-canonical DNA damage response, which we call RING (response induced by a genotoxin), characterized by accumulation of phosphorylated histone H2AX (γH2AX) at the nuclear periphery. RING is the result of persistent DNA damage mediated by toxin nuclease activity and is characterized by hyperphosphorylation of RPA, a sensor of single-stranded D ...[more]

PMID: 31492859

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Project description:Salmonella is one of the most important enteric pathogens worldwide, which is able to cause lethal systemic infection via survival and replication in host macrophages. Lactate, a byproduct of anaerobic or aerobic glycolysis, can induce macrophage M2 polarization, but the relationship between lactate-mediated macrophage M2 polarization and bacterial infection is poorly understood. Here, we evaluated the role of lactate and lactate-mediated macrophage M2 polarization in the pathogenicity of Salmonella. We found that lactate levels were significantly increased in Salmonella-infected macrophages, and the increased lactate was derived from the host. Macrophage and mouse infection assays showed that the addition of lactate enhanced Salmonella replication within macrophages and the colonization of mouse systemic loci, while pharmacological or genetic inhibition of host lactate production impaired Salmonella intracellular replication and its virulence in mice. Further analysis revealed that lactate promotes M2 polarization of Salmonella-infected macrophages, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. Moreover, we showed that macrophage-derived lactate induces the Salmonella pathogenicity island (SPI)-2 type III secretion system, leading to increased translocation of the SPI-2 effector SteE, which is responsible for driving M2 polarization. Overall, these findings suggest that lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization and highlight the complex interactions between Salmonella and macrophages. IMPORTANCE The important enteropathogen Salmonella can cause lethal systemic infection via survival and replication in host macrophages. Lactate represents an abundant intracellular metabolite during bacterial infection, which can also induce macrophage M2 polarization. In this study, we found that macrophage-derived lactate promotes the intracellular replication and systemic infection of Salmonella. During Salmonella infection, lactate via the Salmonella type III secretion system effector SteE promotes macrophage M2 polarization, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. This study highlights the complex interactions between Salmonella and macrophages and provides an additional perspective on host-pathogen crosstalk at the metabolic interface.

Dataset Information

Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection.

Publications

Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection.

Similar Datasets

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