Na
            <sup>+</sup>
            /H
            <sup>+</sup>
            Antiport Is Essential for Yersinia pestis Virulence

Minato, Yusuke; Ghosh, Amit; Faulkner, Wyatt J.; Lind, Erin J.; Bartra, Sara Schesser; Plano, Gregory V.; Jarrett, Clayton O.; Hinnebusch, B. Joseph; Winogrodzki, Judith; Dibrov, Pavel; Häse, Claudia C.

doi:10.1128/iai.00071-13

Cited by 44 publications

(29 citation statements)

References 37 publications

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“…Heparin is highly negatively charged, and is known to bind and inhibit the antibacterial activity of CAMPs (Barań ska- Rybak et al, 2006;Park et al, 2001;Schmidtchen et al, 2001). In addition, heparin was recently shown to be protective for Y. pestis mutants in blood by an unknown mechanism (Minato et al, 2013). Furthermore, the difference in rat versus mouse blood could lead to alterations in host response to Y. pestis, infection prevalence and bacterial loads within the flea (Eisen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

LPS modification promotes maintenance of Yersinia pestis in fleas

et al. 2015

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Yersinia pestis, the causative agent of plague, can be transmitted by fleas by two different mechanisms: by early-phase transmission (EPT), which occurs shortly after flea infection, or by blocked fleas following long-term infection. Efficient flea-borne transmission is predicated upon the ability of Y. pestis to be maintained within the flea. Signature-tagged mutagenesis (STM) was used to identify genes required for Y. pestis maintenance in a genuine plague vector, Xenopsylla cheopis. The STM screen identified seven mutants that displayed markedly reduced fitness in fleas after 4 days, the time during which EPT occurs. Two of the mutants contained insertions in genes encoding glucose 1-phosphate uridylyltransferase (galU) and UDP-4-amino-4-deoxy-Larabinose-oxoglutarate aminotransferase (arnB), which are involved in the modification of lipid A with 4-amino-4-deoxy-L-arabinose (Ara4N) and resistance to cationic antimicrobial peptides (CAMPs). These Y. pestis mutants were more susceptible to the CAMPs cecropin A and polymyxin B, and produced lipid A lacking Ara4N modifications. Surprisingly, an in-frame deletion of arnB retained modest levels of CAMP resistance and Ara4N modification, indicating the presence of compensatory factors. It was determined that WecE, an aminotransferase involved in biosynthesis of enterobacterial common antigen, plays a novel role in Y. pestis Ara4N modification by partially offsetting the loss of arnB. These results indicated that mechanisms of Ara4N modification of lipid A are more complex than previously thought, and these modifications, as well as several factors yet to be elucidated, play an important role in early survival and transmission of Y. pestis in the flea vector.

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Section: Discussionmentioning

confidence: 99%

LPS modification promotes maintenance of Yersinia pestis in fleas

et al. 2015

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“…The circles represent particles and binding sites. which NhaA is essential for the pathogenicity of bacteria (38). Perhaps more importantly, the human equivalent of NhaA, NHE, is associated with a growing number of human pathologies, such as cancer, hypertension, and reperfusion damage, among others (for a review, see ref.…”

Section: Discussionmentioning

confidence: 99%

Simulating the function of sodium/proton antiporters

Alhadeff

Warshel

2015

Proc. Natl. Acad. Sci. U.S.A.

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The molecular basis of the function of transporters is a problem of significant importance, and the emerging structural information has not yet been converted to a full understanding of the corresponding function. This work explores the molecular origin of the function of the bacterial Na + /H + antiporter NhaA by evaluating the energetics of the Na + and H + movement and then using the resulting landscape in Monte Carlo simulations that examine two transport models and explore which model can reproduce the relevant experimental results. The simulations reproduce the observed transport features by a relatively simple model that relates the protein structure to its transporting function. Focusing on the two key aspartic acid residues of NhaA, D163 and D164, shows that the fully charged state acts as an Na + trap and that the fully protonated one poses an energetic barrier that blocks the transport of Na + . By alternating between the former and latter states, mediated by the partially protonated protein, protons, and Na + can be exchanged across the membrane at 2:1 stoichiometry. Our study provides a numerical validation of the need of large conformational changes for effective transport. Furthermore, we also yield a reasonable explanation for the observation that some mammalian transporters have 1:1 stoichiometry. The present coarse-grained model can provide a general way for exploring the function of transporters on a molecular level.transport | computational biology | membrane protein

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“…Recent work has shown that nhaA is required for Y. pestis virulence in murine infections (56). The exact mechanism of this requirement is still unknown, although it has been speculated that it functions to prevent Na toxicity (56).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Analysis of Yersinia enterocolitica Biovar 1B Infecting Murine Macrophages Reveals New Mechanisms of Extracellular and Intracellular Survival

et al. 2015

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c Yersinia enterocolitica is typically considered an extracellular pathogen; however, during the course of an infection, a significant number of bacteria are stably maintained within host cell vacuoles. Little is known about this population and the role it plays during an infection. To address this question and to elucidate the spatially and temporally dynamic gene expression patterns of Y. enterocolitica biovar 1B through the course of an in vitro infection, transcriptome sequencing and differential gene expression analysis of bacteria infecting murine macrophage cells were performed under four distinct conditions. Bacteria were first grown in a nutrient-rich medium at 26°C to establish a baseline of gene expression that is unrelated to infection. The transcriptomes of these bacteria were then compared to bacteria grown in a conditioned cell culture medium at 37°C to identify genes that were differentially expressed in response to the increased temperature and medium but not in response to host cells. Infections were then performed, and the transcriptomes of bacteria found on the extracellular surface and intracellular compartments were analyzed individually. The upregulated genes revealed potential roles for a variety of systems in promoting intracellular virulence, including the Ysa type III secretion system, the Yts2 type II secretion system, and the Tad pilus. It was further determined that mutants of each of these systems had decreased virulence while infecting macrophages. Overall, these results reveal the complete set of genes expressed by Y. enterocolitica in response to infection and provide the groundwork for future virulence studies.T he genus Yersinia includes three species that are pathogenic to humans: Y. pestis, the causative agent of the plague, as well as Y. enterocolitica and Y. pseudotuberculosis, both of which cause gastrointestinal diseases. Of the three organisms, Y. enterocolitica is the species most frequently isolated from humans (1). Y. enterocolitica infections are typically acquired through ingestion of the bacteria in contaminated food or water, especially raw or undercooked pork products (2). After ingestion, the bacteria travel through the gastrointestinal tract to the terminal ileum, where they are able to penetrate the M cells of the Peyer's patches and infect the mesenteric lymph nodes (1-3). This leads to a self-limiting gastroenteritis and mesenteric lymphadenitis in otherwise healthy patients (3). In immunocompromised patients or young children with developing immune systems, the bacteria can spread from the lymph nodes to systemic sites, leading to potentially fatal septicemia (1). Over half of all reported Y. enterocolitica infections occur in children under the age of five, the group that is most predisposed to developing the systemic form of the infection (4).Pathogenic Y. enterocolitica isolates can be divided into six distinct biovars based on several biochemical and physiological attributes (2, 5). Of the six biovars, the North American isolate, biovar 1B, is the most...

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Na ⁺ /H ⁺ Antiport Is Essential for Yersinia pestis Virulence

Cited by 44 publications

References 37 publications

LPS modification promotes maintenance of Yersinia pestis in fleas

LPS modification promotes maintenance of Yersinia pestis in fleas

Simulating the function of sodium/proton antiporters

Transcriptomic Analysis of Yersinia enterocolitica Biovar 1B Infecting Murine Macrophages Reveals New Mechanisms of Extracellular and Intracellular Survival

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Na + /H + Antiport Is Essential for Yersinia pestis Virulence

Cited by 44 publications

References 37 publications

LPS modification promotes maintenance of Yersinia pestis in fleas

LPS modification promotes maintenance of Yersinia pestis in fleas

Simulating the function of sodium/proton antiporters

Transcriptomic Analysis of Yersinia enterocolitica Biovar 1B Infecting Murine Macrophages Reveals New Mechanisms of Extracellular and Intracellular Survival

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Na ⁺ /H ⁺ Antiport Is Essential for Yersinia pestis Virulence