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      Yersinia pestis Requires Host Rab1b for Survival in Macrophages

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          Abstract

          Yersinia pestis is a facultative intracellular pathogen that causes the disease known as plague. During infection of macrophages Y. pestis actively evades the normal phagosomal maturation pathway to establish a replicative niche within the cell. However, the mechanisms used by Y. pestis to subvert killing by the macrophage are unknown. Host Rab GTPases are central mediators of vesicular trafficking and are commonly targeted by bacterial pathogens to alter phagosome maturation and killing by macrophages. Here we demonstrate for the first time that host Rab1b is required for Y. pestis to effectively evade killing by macrophages. We also show that Rab1b is specifically recruited to the Yersinia containing vacuole (YCV) and that Y. pestis is unable to subvert YCV acidification when Rab1b expression is knocked down in macrophages. Furthermore, Rab1b knockdown also altered the frequency of association between the YCV with the lysosomal marker Lamp1, suggesting that Rab1b recruitment to the YCV directly inhibits phagosome maturation. Finally, we show that Rab1b knockdown also impacts the pH of the Legionella pneumophila containing vacuole, another pathogen that recruits Rab1b to its vacuole. Together these data identify a novel role for Rab1b in the subversion of phagosome maturation by intracellular pathogens and suggest that recruitment of Rab1b to the pathogen containing vacuole may be a conserved mechanism to control vacuole pH.

          Author Summary

          Yersinia pestis is the bacterial agent that causes the human disease known as plague. While often considered a historic disease, Y. pestis is endemic in rodent populations on several continents and the World Health Organization considers plague to be a reemerging disease. Much of the success of this pathogen comes from its ability to evade clearance by the innate immune system of its host. One weapon in the Y. pestis arsenal is its ability to resist killing when engulfed by macrophages. Upon invasion of macrophages, Y. pestis actively manipulates the cell to generate a protective vacuolar compartment, called the Yersinia containing vacuole (YCV) that allows the bacterium to evade the normal pathogen killing mechanisms of the macrophage. Here we demonstrate that the host protein Rab1b is recruited to the YCV and is required for Y. pestis to inhibit both the acidification and normal maturation of the phagosome to establish a protective niche within the cell. Rab1b is the first protein, either from the host or Y. pestis, shown to contribute to the biogenesis of the YCV. Furthermore, our data suggest a previously unknown impact of Rab1b recruitment in the phagosome maturation pathway.

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          Lysosomal physiology.

          Lysosomes are acidic compartments filled with more than 60 different types of hydrolases. They mediate the degradation of extracellular particles from endocytosis and of intracellular components from autophagy. The digested products are transported out of the lysosome via specific catabolite exporters or via vesicular membrane trafficking. Lysosomes also contain more than 50 membrane proteins and are equipped with the machinery to sense nutrient availability, which determines the distribution, number, size, and activity of lysosomes to control the specificity of cargo flux and timing (the initiation and termination) of degradation. Defects in degradation, export, or trafficking result in lysosomal dysfunction and lysosomal storage diseases (LSDs). Lysosomal channels and transporters mediate ion flux across perimeter membranes to regulate lysosomal ion homeostasis, membrane potential, catabolite export, membrane trafficking, and nutrient sensing. Dysregulation of lysosomal channels underlies the pathogenesis of many LSDs and possibly that of metabolic and common neurodegenerative diseases.
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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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              Insights into the evolution of Yersinia pestis through whole-genome comparison with Yersinia pseudotuberculosis.

              Yersinia pestis, the causative agent of plague, is a highly uniform clone that diverged recently from the enteric pathogen Yersinia pseudotuberculosis. Despite their close genetic relationship, they differ radically in their pathogenicity and transmission. Here, we report the complete genomic sequence of Y. pseudotuberculosis IP32953 and its use for detailed genome comparisons with available Y. pestis sequences. Analyses of identified differences across a panel of Yersinia isolates from around the world reveal 32 Y. pestis chromosomal genes that, together with the two Y. pestis-specific plasmids, to our knowledge, represent the only new genetic material in Y. pestis acquired since the the divergence from Y. pseudotuberculosis. In contrast, 149 other pseudogenes (doubling the previous estimate) and 317 genes absent from Y. pestis were detected, indicating that as many as 13% of Y. pseudotuberculosis genes no longer function in Y. pestis. Extensive insertion sequence-mediated genome rearrangements and reductive evolution through massive gene loss, resulting in elimination and modification of preexisting gene expression pathways, appear to be more important than acquisition of genes in the evolution of Y. pestis. These results provide a sobering example of how a highly virulent epidemic clone can suddenly emerge from a less virulent, closely related progenitor.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                23 October 2015
                October 2015
                : 11
                : 10
                Affiliations
                [001]Department of Microbiology and Immunology and the Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
                Stanford University School of Medicine, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MGC ARP MBL. Performed the experiments: MGC ARP CTP. Analyzed the data: MGC ARP CTP YAK MBL. Contributed reagents/materials/analysis tools: YAK. Wrote the paper: MGC ARP MBL.

                Article
                PPATHOGENS-D-15-00683
                10.1371/journal.ppat.1005241
                4619670
                26495854
                c1e7b376-8bee-4e09-b77c-88f741d52992

                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

                Page count
                Figures: 8, Tables: 0, Pages: 24
                Product
                Funding
                This work was suported by funding from the National Institutes of Health (AI097608) and The University of Louisville Center for Predictive Medicine to MBL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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