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The GAP Activity of Type III Effector YopE Triggers Killing of Yersinia in Macrophages

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      Abstract

      The mammalian immune system has the ability to discriminate between pathogens and innocuous microbes by detecting conserved molecular patterns. In addition to conserved microbial patterns, the mammalian immune system may recognize distinct pathogen-induced processes through a mechanism which is poorly understood. Previous studies have shown that a type III secretion system (T3SS) in Yersinia pseudotuberculosis leads to decreased survival of this bacterium in primary murine macrophages by unknown mechanisms. Here, we use colony forming unit assays and fluorescence microscopy to investigate how the T3SS triggers killing of Yersinia in macrophages. We present evidence that Yersinia outer protein E (YopE) delivered by the T3SS triggers intracellular killing response against Yersinia. YopE mimics eukaryotic GTPase activating proteins (GAPs) and inactivates Rho GTPases in host cells. Unlike wild-type YopE, catalytically dead YopER144A is impaired in restricting Yersinia intracellular survival, highlighting that the GAP activity of YopE is detected as a danger signal. Additionally, a second translocated effector, YopT, counteracts the YopE triggered killing effect by decreasing the translocation level of YopE and possibly by competing for the same pool of Rho GTPase targets. Moreover, inactivation of Rho GTPases by Clostridium difficile Toxin B mimics the effect of YopE and promotes increased killing of Yersinia in macrophages. Using a Rac inhibitor NSC23766 and a Rho inhibitor TAT-C3, we show that macrophages restrict Yersinia intracellular survival in response to Rac1 inhibition, but not Rho inhibition. In summary, our findings reveal that primary macrophages sense manipulation of Rho GTPases by Yersinia YopE and actively counteract pathogenic infection by restricting intracellular bacterial survival. Our results uncover a new mode of innate immune recognition in response to pathogenic infection.

      Author Summary

      The type III secretion system (T3SS) is a macromolecular protein export pathway found in gram-negative bacteria. It delivers bacterial toxins into eukaryotic cells to promote pathogenic infection. T3SSs and the bacterial toxins delivered are critical arsenals for many bacterial pathogens of clinical significance, such as Yersinia, Salmonella and Shigella. On the other hand, the mammalian immune system may recognize the T3SS as a danger signal to signify pathogenic infection, and to stimulate appropriate defense against pathogens. Here, we show that the innate immune system recognizes the activity of YopE delivered by the Yersinia T3SS. Modulation of host Rho GTPases by YopE elicits a defensive response, which results in killing of bacteria in host cells. Inhibition of host Rho GTPases by Clostridium difficile Toxin B, another bacterial toxin, mimics the YopE-triggered killing effect. Our study demonstrates that host cells sense manipulation of Rho GTPases by bacterial toxins as a surveillance mechanism, revealing new insights into innate immune recognition of pathogenic infections.

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      Most cited references 63

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      The mammalian immune system has innate and adaptive components, which cooperate to protect the host against microbial infections. The innate immune system consists of functionally distinct 'modules' that evolved to provide different forms of protection against pathogens. It senses pathogens through pattern-recognition receptors, which trigger the activation of antimicrobial defences and stimulate the adaptive immune response. The adaptive immune system, in turn, activates innate effector mechanisms in an antigen-specific manner. The connections between the various immune components are not fully understood, but recent progress brings us closer to an integrated view of the immune system and its function in host defence.
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        Mammalian Rho GTPases: new insights into their functions from in vivo studies.

        Rho GTPases are key regulators of cytoskeletal dynamics and affect many cellular processes, including cell polarity, migration, vesicle trafficking and cytokinesis. These proteins are conserved from plants and yeast to mammals, and function by interacting with and stimulating various downstream targets, including actin nucleators, protein kinases and phospholipases. The roles of Rho GTPases have been extensively studied in different mammalian cell types using mainly dominant negative and constitutively active mutants. The recent availability of knockout mice for several members of the Rho family reveals new information about their roles in signalling to the cytoskeleton and in development.
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          Yersinia pestis--etiologic agent of plague.

          Plague is a widespread zoonotic disease that is caused by Yersinia pestis and has had devastating effects on the human population throughout history. Disappearance of the disease is unlikely due to the wide range of mammalian hosts and their attendant fleas. The flea/rodent life cycle of Y. pestis, a gram-negative obligate pathogen, exposes it to very different environmental conditions and has resulted in some novel traits facilitating transmission and infection. Studies characterizing virulence determinants of Y. pestis have identified novel mechanisms for overcoming host defenses. Regulatory systems controlling the expression of some of these virulence factors have proven quite complex. These areas of research have provide new insights into the host-parasite relationship. This review will update our present understanding of the history, etiology, epidemiology, clinical aspects, and public health issues of plague.
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            Author and article information

            Affiliations
            Department of Molecular Genetics and Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, United States of America
            University of California, Davis, United States of America
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: XW JBB. Performed the experiments: XW KP AS. Analyzed the data: XW JBB. Wrote the paper: XW JBB.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, USA )
            1553-7366
            1553-7374
            August 2014
            28 August 2014
            : 10
            : 8
            25165815 4148447 PPATHOGENS-D-14-00511 10.1371/journal.ppat.1004346

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Counts
            Pages: 16
            Funding
            This research was supported by awards from the NIH and NIAID (R01AI099222 and U54AI057158-Lipkin). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Blood Cells
            White Blood Cells
            Macrophages
            Immune Cells
            Immunology
            Clinical Immunology
            Infectious Disease Immunology
            Microbiology
            Medical Microbiology
            Microbial Pathogens
            Bacterial Pathogens
            Yersinia
            Yersinia Pseudotuberculosis

            Infectious disease & Microbiology

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