PLoS http://www.plospathogens.org/ webmaster@plos.org Publishing science info:doi/10.1371/feed.ppat This work is licensed under a Creative Commons Attribution-Share Alike 3.0 License ${webserver-url}images/favicon.ico ${webserver-url}images/favicon.ico 2009-11-20T20:02:15Z Subscribe with My Yahoo!Subscribe with NewsGatorSubscribe with My AOLSubscribe with BloglinesSubscribe with NetvibesSubscribe with GoogleSubscribe with Pageflakes Anthony D. Baughn et al. info:doi/10.1371/journal.ppat.1000662 2009-11-20T08:00:00Z 2009-11-20T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Knowledge of the basic biology of <i>Mycobacterium tuberculosis</i> is essential to identifying novel ways to combat the emerging threat of drug-resistant tuberculosis. Since the tricarboxylic acid (TCA) cycle is a cornerstone of metabolism and <i>M. tuberculosis</i> does not possess a “typical” TCA cycle enzyme set, much effort has been focused on elucidating the components of this pathway. Previous reports indicate that <i>M. tuberculosis</i> possesses a variant TCA cycle in which succinic semialdehyde replaces succinyl-CoA. Since this pathway does not conserve as much metabolic energy as the canonical pathway, we considered an alternative hypothesis: that <i>M. tuberculosis</i> might possess an anaerobic type α-ketoglutarate dehydrogenase. In this manuscript, we investigate this previously unknown activity for mycobacteria using a combination of genetic and biochemical approaches, and demonstrate that <i>M. tuberculosis</i> is capable of driving a conventional TCA cycle in an unconventional way. We also validate the existence of the previously described variant pathway and provide evidence that these two pathways are differentially utilized in response to a metabolic signal, fatty acid catabolism.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/M0OIT9slJFg" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000662 Yoshiharu Yamaichi et al. info:doi/10.1371/journal.ppat.1000663 2009-11-20T08:00:00Z 2009-11-20T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Multi-drug resistant bacteria continue to emerge and there is a pressing need for the development of new antibiotics. Here, we carried out a cell-based high throughput screen to identify inhibitors of RctB, the initiator of replication of the second chromosome found in all the species of the <i>Vibrionaceae</i>. This family of bacteria includes several human pathogens, including <i>Vibrio cholerae</i>, the cause of cholera, as well as several species that damage economically important marine organisms. We identified a compound—designated vibrepin—that has potent cidal activity against <i>V. cholerae</i> and inhibited growth of all vibrio species tested. Vibrepin blocked RctB unwinding of the origin of replication of the second <i>V. cholerae</i> chromosome, apparently by promoting the formation of large non-functional RctB complexes. Vibrepin represents a new class of antibiotic that specifically targets a particular family of microorganisms (the <i>Vibrionaceae</i>). Such targeted agents will not engender resistance in the normal human flora or in non-vibrio environmental microorganisms. Thus, in principle, genes mediating resistance to these compounds will not arise in and be transferred from non-vibrios to vibrios, perhaps postponing the development of resistance.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/fngfzQ_AVF8" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000663 D. Kesley Robertson et al. info:doi/10.1371/journal.ppat.1000664 2009-11-20T08:00:00Z 2009-11-20T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">The genus <i>Chlamydia</i> is composed of a group of obligate intracellular bacterial pathogens that cause several human diseases of medical significance. <i>C. trachomatis</i> is the most commonly encountered sexually transmitted pathogen, as well as the leading cause of preventable blindness worldwide. The prevalence of chlamydial infections, and the extraordinary morbidity and health care costs associated with chronic persisting disease, justifies the research efforts in this area of microbial pathogenesis. Despite their clinical importance, the mechanisms by which these intracellular bacteria obtain nutrients essential to their growth remain enigmatic. Acquisition of sphingolipids, from the cells that chlamydiae infect, is essential for bacterial propagation. This study identifies a requirement for the lipid sphingomyelin from the infected host cell for bacterial replication during infection, and for long-term subsistence in persistent chlamydial infection. Blockage of sphingomyelin acquisition results in premature release of bacteria, a reduced bacterial number, and failure of the bacteria to cause a persisting infection. In this study, we have identified and subsequently disrupted specific sphingomyelin transport pathways, providing important implications on therapeutic intervention targeting this successful microbial pathogen.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/fIewVN1eH4s" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000664 Kathryn M. Monroe et al. info:doi/10.1371/journal.ppat.1000665 2009-11-20T08:00:00Z 2009-11-20T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Initial detection of invading microorganisms is one of the primary tasks of the innate immune system. However, the molecular mechanisms by which pathogens are recognized remain incompletely understood. Here, we provide evidence that an immunosurveillance pathway (called the RIG-I/MDA5 pathway), thought primarily to detect viruses, is also involved in the innate immune response to an intracellular bacterial pathogen, <i>Legionella pneumophila</i>. In the response to viruses, the RIG-I/MDA5 immunosurveillance pathway has been shown to respond to viral RNA or DNA. We found that the RIG-I pathway was required for the response to <i>L. pneumophila</i> RNA, but was not required for the response to <i>L. pneumophila</i> DNA. Thus, one explanation of our results is that <i>L. pneumophila</i> RNA may access the host cell cytosol, where it triggers the RIG-I/MDA5 pathway. This is unexpected since bacteria have not previously been thought to translocate RNA into host cells. We also found that <i>L. pneumophila</i> encodes a secreted bacterial protein, SdhA, which suppresses the RIG-I/MDA5 pathway. Several viral repressors of the RIG-I/MDA5 pathway have been described, but bacterial repressors of RIG-I/MDA5 are not known. Thus, our study provides novel insights into the molecular mechanisms by which the immune system detects bacterial infection, and conversely, by which bacteria suppress innate immune responses.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/DTKq1cJ1pMI" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000665 David R. Taylor et al. info:doi/10.1371/journal.ppat.1000666 2009-11-20T08:00:00Z 2009-11-20T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">The prion diseases are unique in that their infectious nature is not dependent on nucleic acid but is instead attributed to a misfolded protein, the prion protein. This misfolded prion protein is capable of inducing the misfolding of the normal form of the prion protein that is present on the surface of neurons and other cells in the body. However, the site in the cell at which this misfolding occurs and whether other proteins are involved remains controversial. We have addressed these questions by investigating how the normal form of the prion protein is targeted to specialised domains on the plasma membrane termed cholesterol-rich lipid rafts. We show that targeting is due, in part, to a particular heparin sulfate proteoglycan called glypican-1. Significantly, reducing the levels of glypican-1 in an infected cell line reduced the accumulation of misfolded prion protein. We propose that glypican-1 acts as a scaffold facilitating the favourable interaction of the misfolded, infectious form of the prion protein with the normal cellular form within cholesterol-rich lipid rafts. Our results indicate that glypican-1 is intimately involved in the misfolding of the prion protein, the critical event in the pathogenesis of prion diseases such as Creutzfeldt-Jakob disease in humans.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/Bd-CzbqMegs" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000666 Rita Cavaleiro et al. info:doi/10.1371/journal.ppat.1000667 2009-11-20T08:00:00Z 2009-11-20T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Infection by HIV-2, the second AIDS-associated virus, is considered a unique natural model of attenuated HIV disease. HIV-2 infected individuals exhibit much lower levels of circulating virus (viremia) and progress to AIDS at slower rates than HIV-1 infected patients. In this study, we characterized for the first time blood plasmacytoid dendritic cells (pDC), important mediators between innate and acquired immunity, in HIV-2 infection. We observed a profound reduction in circulating pDC levels in HIV-2 infected patients, even in those with undetectable viremia, to levels similar to those found in HIV-1 infection. Moreover, we documented a more differentiated pDC phenotype in both infected cohorts relative to healthy individuals. Despite these similarities between HIV-1 and HIV-2 infections, pDC from HIV-2 patients with undetectable viremia exhibited, upon <i>in vitro</i> stimulation, a better-preserved ability to produce interferon-α (IFN-α), an important anti-viral cytokine with potential to stimulate other immune cells. Overall, our data suggest that the presence of virus in circulation, although not critical for the reduction in pDC number, appears to be central for the impairment of their function. This study of pDC in HIV-2 infection fills a gap in the understanding of their potential role in HIV/AIDS pathogenesis.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/9TLnNMLt1GI" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000667 Olga E. Petrova et al. info:doi/10.1371/journal.ppat.1000668 2009-11-20T08:00:00Z 2009-11-20T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Biofilms are complex communities of microorganisms encased in a matrix and attached to surfaces. It is well recognized that biofilm cells differ from their free swimming counterparts with respect to gene expression, protein production, and resistance to antibiotics and the human immune system. However, little is known about the underlying regulatory events that lead to the formation of biofilms, the primary cause of many chronic and persistent human infections. By mapping the phosphoproteome over the course of <i>P. aeruginosa</i> biofilm development, we identified three novel two-component regulatory systems that were required for the development and maturation of <i>P. aeruginosa</i> biofilms. Activation (phosphorylation) of these three regulatory systems occurred in a sequential manner and inactivation arrested biofilm formation at three distinct developmental stages. Discontinuation of <i>bfiS</i>, <i>bfmR</i>, or <i>mifR</i> expression after biofilms had already matured resulted in disaggregation/collapse of biofilms. Furthermore, this regulatory cascade appears to be linked via BfiS-dependent GacS-phosphorylation to the previously identified LadS/RetS/GacAS/RsmA network that reciprocally regulates virulence and surface attachment. Our data thus indicate the existence of a previously unidentified regulatory program of biofilm development once <i>P. aeruginosa</i> cells have committed to a surface associated lifestyle, and may provide new targets for controlling the programmed differentiation process of biofilm formation.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/Ix2bpkPnFsQ" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000668 Barbara Waidner et al. info:doi/10.1371/journal.ppat.1000669 2009-11-20T08:00:00Z 2009-11-20T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">The human pathogen <i>Helicobacter pylori</i> lives in the hostile environment of the human stomach. <i>H. pylori</i> possesses a spiral shape and high motility that enable the bacterium to swim through the stomach lumen and to come into close contact with epithelial cells. High urease activity in the bacterium counterbalances the low pH within the stomach, in order to persist within the viscous mucus layer. In this work, we analysed the molecular basis of the spiral structure of <i>H. pylori</i>. We demonstrate that the helical cell shape depends on so called <u>c</u>oiled <u>c</u>oil <u>r</u>ich <u>p</u>roteins (Ccrp), which form extended filamentous structures <i>in vitro</i> and <i>in vivo</i>, and are differentially required for the maintenance of proper cell morphology. In most bacteria analysed so far, the actin-like protein MreB affects cell morphology. Contrarily, <i>H. pylori</i> MreB is not involved in the maintenance of cell shape, but affects the progression of the cell cycle. Mutant cells were highly elongated, characteristic for a delay in cell division, and contained non-segregated chromosomes. The persistence of <i>H. pylori</i> in the hostile environment of the human stomach depends on the activity of urease. Interestingly, <i>mreB</i> mutant cells displayed significantly reduced urease activity, revealing a novel connection between the cytoskeletal element and an enzyme, and thus with pathogenicity. These experiments show that <i>H. pylori</i> has a novel type of system setting up helical cell shape, which has not yet been described for any bacterium. Our work will allow studying <i>H. pylori</i> cell cycle and pathogenicity at a new visual level.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/g_ez26oPq9k" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000669 Sheree E. Osborne et al. info:doi/10.1371/journal.ppat.1000656 2009-11-13T08:00:00Z 2009-11-13T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Many human, animal and plant viruses are transmitted between hosts by insect vectors. Understanding the processes that control virus infection in insects may facilitate strategies that aim to control the spread of important viral pathogens. Infection of the model insect <i>Drosophila</i> with the endosymbiotic bacteria <i>Wolbachia</i> can significantly affect the outcome of infection with pathogenic viruses. <i>Wolbachia</i> is widespread in insects, so here we tested the generality of antiviral protection across diverse strains of the bacteria. We show that some, but not all, strains of <i>Wolbachia</i> protect flies from pathogenic viruses. These results have implications for proposed strategies utilising <i>Wolbachia</i> to control the spread of insect-transmitted viral diseases, such as dengue.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/BpCuKSFMKeA" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000656 Ilhem Messaoudi et al. info:doi/10.1371/journal.ppat.1000657 2009-11-13T08:00:00Z 2009-11-13T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Varicella zoster virus (VZV) is a ubiquitous herpesvirus that causes chickenpox (varicella) and establishes a life-long latent infection in humans. VZV can then reactivate causing herpes zoster, commonly known as shingles, a painful and debilitating disease that can be life-threatening in elderly and immunocompromised individuals. Our understanding of immunological factors that control VZV replication is limited due to the fact that VZV causes disease only in humans. Simian varicella virus (SVV) is a simian counterpart of VZV that infects nonhuman primates. Our study showed for the first time that infection of rhesus macaques with SVV recapitulates key aspects of VZV infection from chickenpox and the resolution of acute viremia to the establishment of latency in ganglia, and the development of B and T cell responses to virus. This model will allow us to improve our understanding of the immune response to varicella virus, and to develop and test vaccines and antiviral drugs that can reduce the incidence of shingles and its attendant neurological complications.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/AsPH4woEZPA" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000657 Celia Perales et al. info:doi/10.1371/journal.ppat.1000658 2009-11-13T08:00:00Z 2009-11-13T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">RNA viruses are associated with many important human and animal diseases such as AIDS, influenza, hemorrhagic fevers and several forms of hepatitis. RNA viruses mutate at very high rates and, therefore, can adapt easily to environmental changes. Viral mutants resistant to antiviral inhibitors are readily selected, resulting in treatment failure. The simultaneous administration of three or more inhibitors is a means to prevent or delay selection of resistant mutants. A new antiviral strategy termed lethal mutagenesis is presently under investigation. It consists of the administration of mutagenic agents to elevate the mutation rate of the virus above the maximum level compatible with virus infectivity, without mutagenizing the host cells. Since low amounts of virus are extinguished more easily, the combination of a mutagen and inhibitor was more efficient than a mutagen alone in driving virus to extinction. Here we show that foot-and-mouth disease virus replicating in cell culture can be extinguished more easily when the inhibitor guanidine is administered first, followed by the mutagenic agent ribavirin, than when both drugs are administered simultaneously. Interfering mutants that contribute to extinction were active in the presence of ribavirin but not in the presence of guanidine. This observation provides a mechanism for the advantage of the sequential versus the combination treatment. This unexpected effectiveness of a sequential treatment is supported by a theoretical model of virus evolution in the presence of the inhibitor and the mutagen. The results can have an application for future lethal mutagenesis protocols and for current antiviral treatments that involve the antiviral agent ribavirin when it acts as a mutagen.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/nBamgi5Ofu0" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000658 Tereance A. Myers et al. info:doi/10.1371/journal.ppat.1000659 2009-11-13T08:00:00Z 2009-11-13T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Lyme disease, which is transmitted to humans through the bite of a tick, is currently the most frequently reported vector-borne illness in the northern hemisphere. <i>Borrelia burgdorferi</i> is the bacterium that causes Lyme disease and it is known to readily induce inflammation within a variety of infected tissues. Many of the neurological signs and symptoms that may affect patients with Lyme disease have been associated with <i>B. burgdorferi</i>-induced inflammation in the central nervous system (CNS). In this report we investigated which of the primary cell types residing in the CNS might be functioning to create the inflammatory environment that, in addition to helping clear the pathogen, could simultaneously be harming nearby neurons. We report findings that implicate microglia, a macrophage cell type in the CNS, as the key responders to infection with <i>B. burgdorferi.</i> We also present evidence indicating that this organism is not directly toxic to neurons; rather, a bystander effect is generated whereby the inflammatory surroundings created by microglia in response to <i>B. burgdorferi</i> may themselves be toxic to neuronal cells.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/5ISP-yIQaR0" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000659 Christoph M. Ernst et al. info:doi/10.1371/journal.ppat.1000660 2009-11-13T08:00:00Z 2009-11-13T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Certain bacterial immune-evasion factors such as the MprF protein are highly conserved in many bacterial pathogens and represent attractive targets for new ‘anti-virulence’ drugs. MprF, initially discovered in the major human pathogen <i>Staphylococcus aureus</i>, protects bacteria against ‘innate human antibiotics’ such as the defensin peptides. In addition, MprF has recently been implicated in resistance to the new defensin-like antibiotic daptomycin. MprF modifies bacterial membrane lipids with the amino acid <small>L</small>-lysine, which leads to electrostatic repulsion of the membrane-damaging peptides. The molecular mechanism of MprF has remained largely unknown. We demonstrate that MprF represents a novel bifunctional type of enzyme. The N- and C-terminal domains of MprF are both required for mediating antimicrobial peptide resistance but they can be expressed as two separate proteins without loss of function indicating that they represent distinct functional modules. While the C-terminal domain accomplishes lipid lysinylation the N-terminal membrane-embedded domain is required to expose the lysine lipid at the outer surface of the bacterial membrane where it is able to repulse the antimicrobial peptides. These findings unravel the molecular basis of an important bacterial immune evasion mechanism and they may help to employ MprF as a target for new anti-virulence drugs.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/jHCEA0CzGRg" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000660 Martin P. Hosking et al. info:doi/10.1371/journal.ppat.1000648 2009-11-06T08:00:00Z 2009-11-06T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Consequences of viral infection of the central nervous system (CNS) can range from encephalitis and paralytic poliomyelitis to relatively benign infections with limited clinical outcomes. The localized expression of proinflammatory chemokines within the CNS in response to viral infection has been shown to be important in host defense by attracting antigen-specific lymphocytes from the microvasculature into the parenchyma that control and eventually eliminate the replicating pathogen. However, the relationship between chemokine expression and recruitment of myeloid cells, <i>e.g.</i> neutrophils, to the CNS following infection with a neurotropic virus is not well characterized. Emerging evidence has indicated that the mobilization of neutrophils into the blood and recruitment to the CNS following microbial infection or injury contributes to permeabilization of the blood-brain-barrier that subsequently allows entry of inflammatory leukocytes. Therefore, we have defined the chemokines involved in promoting the directional migration of neutrophils to the CNS in response to viral infection. Using the neurotropic JHM strain of mouse hepatitis virus (JHMV) as a model of acute viral encephalomyelitis, we demonstrate a previously unappreciated role for members of the ELR-positive CXC chemokine family in host defense by attracting PMNs bearing the receptor CXCR2 to the CNS in response to viral infection.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/XMgwy9mee78" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000648 Peyman Nakhaei et al. info:doi/10.1371/journal.ppat.1000650 2009-11-06T08:00:00Z 2009-11-06T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">RNA virus infection is detected through TLR-dependent and TLR-independent mechanisms. Early viral replicative intermediates are detected by two recently characterized cystolic viral RNA receptors, RIG-I and MDA-5, leading to the production of pro-inflammatory cytokines and type I interferons (IFNs). Dysfunctional responses, either failure to respond or hyper-responsiveness, may lead to both acute and chronic immunodeficiency and inflammatory diseases. Thus, the intensity and duration of RLR signaling must be tightly controlled. One general mechanism by which innate immune receptors and their downstream adapters are regulated involves protein degradation mediated by the ubiquitination pathway. Our study demonstrates that the E3 ubiquitin ligase Triad3A negatively regulates the RIG-I-like receptor pathway by targeting the adapter molecule TRAF3 for proteasomal degradation through Lys⁴⁸-linked ubiquitin-mediated degradation. Thus, Triad3A represents a key molecule involved in the negative regulation of the host antiviral response triggered by RNA virus infection.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/dikCel0AbM8" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000650 Ilia Belotserkovsky et al. info:doi/10.1371/journal.ppat.1000651 2009-11-06T08:00:00Z 2009-11-06T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Cell-to-cell communication in bacteria is termed quorum-sensing (QS), which is triggered by signaling molecules called autoinducers. In streptococci, autoinducers are synthesized as immature peptides that are processed, secreted, and then sensed by two-component systems (TCSs). As a result, the autoinducer's own expression is upregulated (autoinduction), subsequently creating an ultrasensitive switch that turns on more genes. Group A streptococcus (GAS) is a human pathogen that causes many infections, including necrotizing fasciitis (NF). Previously, we identified in a NF GAS strain a QS locus termed streptococcal invasion locus (<i>sil</i>). Due to a mutation in the autoinducer peptide-SilCR, it is not produced by this strain. Here we sought to better explore <i>sil</i> and to examine if SilCR can be produced by other GAS strains, or strains of its close relative group G streptococcus (GGS). To this end, we characterized the DNA promoter region responsible for the TCS-mediated activation upon sensing of SilCR, and based on bioinformatics and transcriptome analyses we identified genes that are directly affected by the autoinducer peptide. By converting SilCR response to fluorescence production and turning on the autoinduction circle with minute concentrations of synthetic SilCR, we discovered naturally SilCR-producing GAS and GGS strains, and showed that SilCR can be sensed across these species. Our study describes a novel way of cell-to-cell communications among streptococci.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/jVGLpBSyj4M" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000651 Sergey Ivanchenko et al. info:doi/10.1371/journal.ppat.1000652 2009-11-06T08:00:00Z 2009-11-06T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Human immunodeficiency virus (HIV) particles are formed and released at the plasma membrane of the infected cell. Here, we analyzed the dynamics of HIV assembly and release making use of fluorescently labeled HIV structural proteins. We determined that assembly of the viral protein shell occurs within ~8–9 min after nucleation of an assembly site and virus particles are formed individually and not from large patches. Virion release was observed ~25 min after nucleation of the assembly site. Assembly of the Gag shell thus appears to constitute only a minor part of the period required for particle formation indicating that traversing the membrane and fission are the rate-limiting stages in virion formation. Using a photoconvertible label in the viral Gag protein, we established that the Gag molecules driving nucleation of a new assembly site and in bud growth are recruited preferentially from the cytosolic pool of Gag molecules and from recently membrane-attached Gag. No intracellular assembly or vesicular trafficking of Gag was observed. The described results add essential dynamic information to our picture of virus release and provide an experimental basis for interfering with this stage of virus replication.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/GIhWI2Du2-s" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000652 Kwang-Hyung Kim et al. info:doi/10.1371/journal.ppat.1000653 2009-11-06T08:00:00Z 2009-11-06T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">The critical roles of reactive oxygen species (ROS) in fungal development and virulence have been well established over the past half a century since the first experimental detection of hydrogen peroxide in fungal cells by Bach (1950). In the cell, ROS act as signaling molecules regulating physiological responses and developmental processes and are also involved in sophisticated virulence processes for many pathogenic fungi. Therefore, uncovering the biological roles of cellular ROS appears to be very important in understanding fungal development and virulence. Currently we have limited knowledge of how intracellular ROS are generated by fungal cells and which cellular ROS regulatory mechanisms are involved in establishing homeostasis. In this study we describe a novel protein, TmpL, involved in development and virulence in both plant and animal pathogenic fungi. In the absence of TmpL, dysregulation of oxidative stress homeostasis in both fungi caused developmental and virulence defects. Therefore, elucidating the role of TmpL presents an opportunity to uncover a common pathogenicity mechanism employed by both plant and animal pathogens and to develop efficient and novel therapeutics for both plant and animal fungal disease. Our findings provide new insights into mechanisms underlying the complex web of interactions between ROS and cell differentiation and the involvement of ROS for both plant and animal fungal pathogenesis.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/Y3gRhBBbKxk" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000653 Yohei Watanabe et al. info:doi/10.1371/journal.ppat.1000654 2009-11-06T08:00:00Z 2009-11-06T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">All viruses rely on host cell factors to complete their life cycles. Therefore, the replication strategies of viruses may provide not only the understanding of virus pathogenesis but also useful models to disentangle the complex machinery of host cells. Translation regulation of viral mRNA is a good example of this. Borna disease virus (BDV) is a highly neurotropic RNA virus which is characterized by persistent infection. BDV expresses mRNAs as polycistronic coding transcripts. Among them, the 0.8 kb X/P mRNA encodes at least three open reading frames (ORFs), upstream ORF, X, and P. Although BDV X and P have opposing effects in terms of viral polymerase activity, the translational regulation of X/P polycistronic mRNA has not been elucidated. In this study, we show an ingenious strategy of translational control of viral regulatory protein using host factors. We demonstrate that host RNA helicases, mainly DDX21, can affect ribosomal reinitiation of X via interaction with the 5′ untranslated region (UTR) of X/P mRNA and that the downstream P protein autogenously controls the translation of X by interfering with the binding of DDX21 to the 5′ UTR. Our findings uncover not only a unique translational control of viral regulatory protein but also a previously unknown mechanism of translational regulation of polycistronic mRNA using RNA helicases.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/k5qy-pcUtY8" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000654 David Bond et al. info:doi/10.1371/journal.ppat.1000655 2009-11-06T08:00:00Z 2009-11-06T08:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Innate immunity is the sole immune response in the overwhelming majority of multicellular organisms and drives the sophisticated antigen-specific adaptive defenses of vertebrates. Defective regulation of immune signal transduction pathways has disastrous consequences for affected individuals and can result in life-threatening conditions that include cancer, autoimmune and neurological conditions. Thus, there is a major need to identify the regulatory circuits that govern activation of critical innate immune response pathways. The genetically accessible model organism <i>Drosophila melanogaster</i> is an ideal springboard for such studies, as core aspects of innate immune pathways are evolutionarily conserved and novel discoveries in <i>Drosophila</i> often inspire subsequent developments in the characterization of biomedically relevant mammalian pathways. <i>Drosophila</i> responses to certain bacterial invaders proceed through the IMD pathway, which contains partially overlapping signal transduction JNK and NF-κB arms. While substantial efforts have illuminated much of the NF-κB arm, there is a considerable paucity of information on the regulation of the JNK arm. We conducted a survey of the entire <i>Drosophila</i> genome for novel regulators the Imd/dJNK pathway. In this study, we uncovered a novel link between the proliferative Pvr pathway and the IMD pathway.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/jX_fxjHdIuk" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000655 info:doi/10.1371/image.ppat.v05.i10 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z <b xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">An intimate relationship.</b> <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML"><i>Chlamydia trachomatis</i> is the leading cause of the preventable blindness trachoma worldwide and a major cause of sexually transmitted disease in developed countries. Hidden within the confines of an intracellular niche (shown), the bacterium wields its armament of defense, evasion, and procurement strategies. Rejman Lipinski et al. reveal another snippet of the <i>Chlamydia</i>–host cross-talk, demonstrating that distinct host Rab proteins are essential for the stability of the Golgi apparatus, a key host organelle intimately linked with infection outcome. Such insights will hopefully further broaden the options for the development of novel anti-chlamydial treatments (see <a href="http://dx.doi.org/10.1371/journal.ppat.1000615">Rejman Lipinski et al.</a>, doi:10.1371/journal.ppat.1000615).</p><p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML"><i>Image Credit: Volker Brinkmann, Max Planck Institute for Infection Biology</i></p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/jsOnBW5pS-k" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fimage.ppat.v05.i10 Wilbert Bitter et al. info:doi/10.1371/journal.ppat.1000507 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z <img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/QppC_X08ZG0" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000507 Anthony A. Holder info:doi/10.1371/journal.ppat.1000638 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z <img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/S-aj_uC9bnM" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000638 Constantin F. Urban et al. info:doi/10.1371/journal.ppat.1000639 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Neutrophils are phagocytes that disarm and kill microbes by engulfing them. Less well characterized than their phagocytic killing mechanisms is how neutrophils cope with microbes that are too large to be internalized. Notably, neutrophils may also kill or inhibit extracellularly by releasing Neutrophil Extracellular Traps (NETs). NETs are fibers made of chromatin (histones and DNA) decorated with antimicrobial proteins. NETs ensnare and kill microbes, such as bacteria, fungi and parasites. We wanted to find out if and how NETs control pathogenic fungi that can form large filaments such as <i>Candida albicans</i>. We purified all NET-bound proteins and identified 24 of them. We found that calprotectin is the major antifungal NET-bound protein. Calprotectin was known to be antimicrobial but here we demonstrate that NET formation is a novel release mechanism for this cytoplasmic protein. The NET matrix comes in close contact with the fungi and the high local concentration of calprotectin in the NETs supports the antifungal activity. Furthermore, in mice calprotectin is essential for an efficient antifungal response to <i>Candida albicans</i> in skin, lung and systemic infections. In tissue sections from these animals we detected NETs and NET-associated calprotectin. Thus, our study gives more insights into mechanisms how the immune system copes with fungal pathogens.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/nRkwsk8EAQ4" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000639 Kelly M. McCarthy et al. info:doi/10.1371/journal.ppat.1000640 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Alpha-herpesviruses, including human herpes simplex virus 1 and 2, varicella zoster virus and swine pseudorabies virus, infect the peripheral nervous system of their hosts. Symptoms often include itching, numbness, or pain. Understanding of the physiological basis for these characteristic sensory and motor anomalies remains limited. To provide more insight, we examined the electrical activity of infected neurons in culture. We used pseudorabies virus (PRV) because infected animals show strain dependent, and often, dramatic symptoms (violent scratching and self mutilation). We found that infected neurons exhibited increased action potential (AP) rates. Infected neurons also became electrically coupled, proceeding from small molecular weight dye sharing and coupled activity to large molecular weight dye sharing and complete electrical synchrony. Late in infection, cell bodies fused to form syncytia. When neurons were infected with a virulent strain that could not express glycoprotein B, a member of the viral membrane fusion complex, AP rates were not increased. Changes in electrical connectivity and dye transfer were not observed, and syncytia did not occur. These results suggest that infection induced elevated activity and electrical coupling result from virally induced membrane fusion and may underlie neurological symptoms observed during infection.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/IFI6OhsEX1M" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000640 James C. Charity et al. info:doi/10.1371/journal.ppat.1000641 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Guanosine tetraphosphate (ppGpp) is a small molecule that is produced by many different bacteria in response to nutrient limitation. Although ppGpp has been shown to play an important role in controlling the expression of virulence genes in several pathogenic bacteria, few studies have addressed how this occurs. Here we show that in the intracellular pathogen <i>F. tularensis</i>, ppGpp plays a critical role in controlling the expression of genes required for intracellular replication and virulence, and we uncover the molecular basis for its effect. In particular, we show that ppGpp works in concert with three other essential regulators of virulence gene expression in <i>F. tularensis</i>—a putative DNA-binding protein that we have called PigR and the SspA protein family members MglA and SspA. Our study provides evidence that ppGpp functions to promote the interaction between PigR and a component of <i>F. tularensis</i> RNA polymerase (RNAP) comprising the MglA and SspA proteins. By influencing the interaction between PigR and the RNAP-associated MglA-SspA complex, ppGpp serves to tie the nutritional status of the cell to the expression of genes that are essential for survival in the host.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/whbFkBW_LyU" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000641 Katharine N. Bossart et al. info:doi/10.1371/journal.ppat.1000642 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Nipah virus and Hendra virus are closely related and highly pathogenic zoonoses whose primary natural reservoirs are several species of <i>Pteropus</i> fruit bats. Both Nipah and Hendra viruses can cause severe and often fatal disease in a variety of mammalian hosts, including humans. The henipaviruses are categorized as biosafety level 4 (BSL-4) agents, which has limited the development of animal models and the testing of potential therapeutics and vaccine countermeasures. We show here a new ferret model of Nipah virus pathogenesis in which the underlying pathology closely mirrors the illness seen in Nipah virus-infected humans, including both respiratory and neurological disease. We also show that m102.4, a cross-reactive neutralizing human monoclonal antibody that targets the viral attachment glycoprotein, completely protected ferrets from disease when given ten hours after a lethal Nipah virus challenge. This study is the first successful and viable post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/k-_8e3Q4dvQ" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000642 Yukio Hirayama et al. info:doi/10.1371/journal.ppat.1000643 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML"><i>Mycobacterium tuberculosis</i> and <i>Mycobacterium bovis</i> are major bacterial pathogens that kill approximately 2 million people annually by causing tuberculosis. The <i>M. tuberculosis</i> complex has several strategies to parasitize the host. After infection is established, these pathogens are rarely eliminated from the host, and nowadays approximately a third of the world's human population is infected with the <i>Mycobacterium tuberculosis</i> complex. The elucidation of the parasitic mechanisms of the <i>M. tuberculosis</i> complex is important for the development of novel strategies against the disease. The major portal entry of <i>M. tuberculosis</i> complex is through the respiratory tract. On the surface of the airway, hyaluronan retains bactericidal enzymes so that they are “ready-to-use”, protecting tissues from invading pathogens. Furthermore, fragmented hyaluronan produced as a result of infection is used by the immune system as a sensor of infection. Thus, hyaluronan plays a pivotal role in host defenses in the respiratory tract. However, in this study, we observed that the <i>M. tuberculosis</i> complex utilizes hyaluronan as a carbon source for multiplication. We also found that the <i>M. tuberculosis</i> complex has hyaluronidase activity and showed that it is critical for hyaluronan-dependent growth of the <i>M. tuberculosis</i> complex. This study demonstrates a novel parasitic mechanism of the <i>M. tuberculosis</i> complex and suggests that mycobacterial hyaluronidase is a potential drug target.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/pJWCDIQQGQ4" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000643 Margaret J. Mackinnon et al. info:doi/10.1371/journal.ppat.1000644 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Malaria parasites are particularly good at adapting to the variable environments they encounter during their life cycle. This property helps explain their widespread prevalence and persistence despite massive malaria control campaigns. The genes responsible for this adaptability are largely unknown. In this study we analyzed gene expression profiles of <i>P. falciparum</i> parasites recently taken from the field and compared them to those from laboratory-adapted parasites. Many of the genes that were up-regulated in field isolates coded for proteins which are exported, or involved in export, from the parasite onto the surface of the host cell where they interact with the immune system. Differences at the expression level were partly explainable by variation in gene copy number caused by deletions or amplification of small chromosomal segments. Usually, higher gene copy was associated with elevated expression levels, but for some genes, more copies appeared to repress expression. Remarkably, the regulatory effects of deleted or amplified segments appeared to extend to genes outside the segment boundaries. This suggests an epigenetically mediated co-regulation of tightly linked gene clusters. Such ‘soft-wired’, coordinated adaptation is potentially an important mechanism by which the parasite readily adapts to its current host. The molecules responsible may therefore be important targets for drugs or vaccines.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/rT2gXtyetkk" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000644 Thierry Christophe et al. info:doi/10.1371/journal.ppat.1000645 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Tuberculosis is still a major threat to global health. The disease in humans is caused by a bacterium, <i>Mycobacterium tuberculosis</i>, and treatment of an infected individual requires more than six months of chemotherapy. Because such a long course of treatment is required, compliance is low, which can result in the development of multidrug resistant strains (MDR-TB) and even extremely resistant strains (XDR-TB). Identifying new drug targets and potential lead therapeutic compounds are needed to combat MDR-XDR-TB. We developed a new type of assay based on the visualization of mycobacterium replication within host cells and applied it for the search of compounds that are able to chase the pathogen from its hideout. As a result, we found 20 new series of drug candidates that are effective against the bacilli in its hiding place, potentially addressing a crucial aspect in the resilience of the disease. We also showed that one series of compounds acts by inhibiting a key enzyme required for the synthesis of an essential component from the mycobacterial cell wall that is not targeted by any of the commercially available antituberculosis drugs. Altogether, our results pave the way for development of the next generation of antibacterial agents.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/f3JCrwyqzvM" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000645 Joseph P. Casazza et al. info:doi/10.1371/journal.ppat.1000646 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">HIV infection results in a significant loss of CD4⁺ T cells, particularly HIV-specific CD4⁺ T cells. In contrast to this, CMV-specific CD4⁺ T cells persist in large numbers, even in individuals with AIDS. We compared the functional profile of HIV-specific and CMV-specific CD4⁺ T cells and found that unlike HIV-specific CD4⁺ T cells, CMV-specific CD4⁺ T cells rapidly produce MIP-1β when stimulated with cognate antigen. CMV specific CD4⁺ T cells also produce another β chemokine when stimulated with cognate antigen, MIP-1α. Addition of both of these chemokines to <i>in vitro</i> incubations protects CD4⁺ T cells from HIV infection. To determine if the production of these two chemokines could protect the CD4⁺ T cells that produce them <i>in vivo</i>, we analyzed peripheral blood cells from HIV infected individuals and separated CMV-specific CD4⁺ T cells that produced MIP-1β from CMV-specific CD4⁺ T cells that did not. We found that cells that produced MIP-1β were less frequently infected with HIV than those that did not produce MIP-1β. These data, and recent advances in vaccine design, suggest that it may be possible to design a vaccine in which vaccine-induced HIV-specific CD4⁺ T cells are less susceptible to infection than those usually produced during HIV infection.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/ldMM9dsj3L8" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000646 Helen J. Wearing et al. info:doi/10.1371/journal.ppat.1000647 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">The eradication of vaccine-preventable infectious diseases remains an important public health priority. To achieve this goal, the level of immunity afforded needs to be high and long-lasting. For pertussis, one of the leading causes of mortality in infants, immunity has been shown to wane in some individuals. The epidemiological impacts of this observation depend critically on the duration of protective immunity in the entire population, which remains notoriously difficult to estimate. We approach this problem by exploring the agreement between model dynamics and case notification data from England &amp; Wales. Our estimates suggest the average duration of immunity is much longer than is currently thought (at least 30 years), but that some individuals would lose immunity quite rapidly.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/CKnhoPgYwzQ" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000647 Elizabeth A. Winzeler info:doi/10.1371/journal.ppat.1000649 2009-10-30T07:00:00Z 2009-10-30T07:00:00Z <img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/QtnoNxeJBvU" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000649 Marion S. Dorer et al. info:doi/10.1371/journal.ppat.1000544 2009-10-26T07:00:00Z 2009-10-26T07:00:00Z <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">The discovery of a bacterium, <i>Helicobacter pylori</i>, that is resident in the human stomach and causes chronic disease (peptic ulcer and gastric cancer) was radical on many levels. Whereas the mouth and the colon were both known to host a large number of microorganisms, collectively referred to as the microbiome, the stomach was thought to be a virtual Sahara desert for microbes because of its high acidity. We now know that <i>H. pylori</i> is one of many species of bacteria that live in the stomach, although <i>H. pylori</i> seems to dominate this community. <i>H. pylori</i> does not behave as a classical bacterial pathogen: disease is not solely mediated by production of toxins, although certain <i>H. pylori</i> genes, including those that encode exotoxins, increase the risk of disease development. Instead, disease seems to result from a complex interaction between the bacterium, the host, and the environment. Furthermore, <i>H. pylori</i> was the first bacterium observed to behave as a carcinogen. The innate and adaptive immune defenses of the host, combined with factors in the environment of the stomach, apparently drive a continuously high rate of genomic variation in <i>H. pylori</i>. Studies of this genetic diversity in strains isolated from various locations across the globe show that <i>H. pylori</i> has coevolved with humans throughout our history. This long association has given rise not only to disease, but also to possible protective effects, particularly with respect to diseases of the esophagus. Given this complex relationship with human health, eradication of <i>H. pylori</i> in nonsymptomatic individuals may not be the best course of action. The story of <i>H. pylori</i> teaches us to look more deeply at our resident microbiome and the complexity of its interactions, both in this complex population and within our own tissues, to gain a better understanding of health and disease.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/gOHxLvy173U" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000544 Bart L. Haagmans et al. info:doi/10.1371/journal.ppat.1000557 2009-10-26T07:00:00Z 2009-10-26T07:00:00Z <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Interspecies transmission of pathogens may result in the emergence of new infectious diseases in humans as well as in domestic and wild animals. Genomics tools such as high-throughput sequencing, mRNA expression profiling, and microarray-based analysis of single nucleotide polymorphisms are providing unprecedented ways to analyze the diversity of the genomes of emerging pathogens as well as the molecular basis of the host response to them. By comparing and contrasting the outcomes of an emerging infection with those of closely related pathogens in different but related host species, we can further delineate the various host pathways determining the outcome of zoonotic transmission and adaptation to the newly invaded species. The ultimate challenge is to link pathogen and host genomics data with biological outcomes of zoonotic transmission and to translate the integrated data into novel intervention strategies that eventually will allow the effective control of newly emerging infectious diseases.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/ibY-67wV7Uw" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000557 Alice Carolyn McHardy et al. info:doi/10.1371/journal.ppat.1000566 2009-10-26T07:00:00Z 2009-10-26T07:00:00Z <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Influenza A virus causes annual epidemics and occasional pandemics of short-term respiratory infections associated with considerable morbidity and mortality. The pandemics occur when new human-transmissible viruses that have the major surface protein of influenza A viruses from other host species are introduced into the human population. Between such rare events, the evolution of influenza is shaped by antigenic drift: the accumulation of mutations that result in changes in exposed regions of the viral surface proteins. Antigenic drift makes the virus less susceptible to immediate neutralization by the immune system in individuals who have had a previous influenza infection or vaccination. A biannual reevaluation of the vaccine composition is essential to maintain its effectiveness due to this immune escape. The study of influenza genomes is key to this endeavor, increasing our understanding of antigenic drift and enhancing the accuracy of vaccine strain selection. Recent large-scale genome sequencing and antigenic typing has considerably improved our understanding of influenza evolution: epidemics around the globe are seeded from a reservoir in East-Southeast Asia with year-round prevalence of influenza viruses; antigenically similar strains predominate in epidemics worldwide for several years before being replaced by a new antigenic cluster of strains. Future in-depth studies of the influenza reservoir, along with large-scale data mining of genomic resources and the integration of epidemiological, genomic, and antigenic data, should enhance our understanding of antigenic drift and improve the detection and control of antigenically novel emerging strains.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/B1GW5dFqLFk" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000566 Iñaki Comas et al. info:doi/10.1371/journal.ppat.1000600 2009-10-26T07:00:00Z 2009-10-26T07:00:00Z <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Renewed efforts in tuberculosis (TB) research have led to important new insights into the biology and epidemiology of this devastating disease. Yet, in the face of the modern epidemics of HIV/AIDS, diabetes, and multidrug resistance—all of which contribute to susceptibility to TB—global control of the disease will remain a formidable challenge for years to come. New high-throughput genomics technologies are already contributing to studies of TB's epidemiology, comparative genomics, evolution, and host–pathogen interaction. We argue here, however, that new multidisciplinary approaches—especially the integration of epidemiology with systems biology in what we call “systems epidemiology”—will be required to eliminate TB.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/bOE6vy5SwUs" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000600 Vera Kozjak-Pavlovic et al. info:doi/10.1371/journal.ppat.1000629 2009-10-23T07:00:00Z 2009-10-23T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">PorB is a bacterial porin that plays an important role in the pathogenicity of <i>Neisseria gonorrhoeae</i>. Upon infection with these bacteria, PorB is transported into mitochondria of infected cells, causing the loss of mitochondrial membrane potential and eventually leading to apoptotic cell death. Here, we show that PorB enters mitochondria through the TOM complex, similar to other mitochondria-targeted proteins, but then bypasses the SAM complex machinery that assembles all other porin-like proteins into the outer mitochondrial membrane. This leads to the accumulation of PorB in the intermembrane space and the integration of a fraction of PorB into the inner mitochondrial membrane (IMM). In the IMM, ATP-regulated pores are formed, leading to dissipation of membrane potential and the loss of cristae structure in affected mitochondria, the necessary first steps in induction of apoptosis. Our work offers, for the first time, a detailed analysis of the mechanism by which PorB targets and damages host cell mitochondria.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/jvL5SAX6YS8" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000629 Natacha Kremer et al. info:doi/10.1371/journal.ppat.1000630 2009-10-23T07:00:00Z 2009-10-23T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML"><i>Wolbachia</i> are intracellular bacteria that infect numerous invertebrate species, where they are generally facultative for their host. Surprisingly, the wasp <i>Asobara tabida</i> is dependent on <i>Wolbachia</i> for egg production: in uninfected females, the cells necessary for egg maturation die prematurely as a result of apoptosis. When we analyzed the genetic basis of this dependence, we found that ferritin, a protein involved in the regulation of iron homeostasis, was over-expressed in uninfected individuals. We also found that <i>Wolbachia</i> interferes with iron metabolism and ferritin expression in other host–<i>Wolbachia</i> associations. Furthermore, <i>Wolbachia</i> itself responds to changes in iron concentration by changing the expression of bacterioferritin. Iron is in short supply within the cell, and is necessary for both host and symbiont; our findings highlight the key role of iron in host–symbiont interactions, as had previously been shown for host–pathogen interactions. Furthermore, iron homeostasis is involved in the regulation of oxidative stress, which in turn is involved in inducing cell death. <i>Wolbachia</i> could also interfere with iron in a way that limits oxidative stress and cell death, thus promoting its persistence within host cells. In <i>A. tabida</i>, we show that iron induced cell death in the ovaries, suggesting that iron metabolism could also be linked to the evolution of dependence.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/sZRdMAECeM0" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000630 Pattamawan Chimma et al. info:doi/10.1371/journal.ppat.1000631 2009-10-23T07:00:00Z 2009-10-23T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Blood monocytes (MO) belong to the first line of defense against infectious pathogens, but little is known of MO phenotype and function during acute malaria infection. In patients with acute uncomplicated malaria, we identified a unique, and so far not described, minor population of MO. The percentage and absolute number of MO with this unusual phenotype was high in patients with low level of blood parasitemia, suggesting that activation of this particular subset of blood MO was potentially associated with the control of parasite infection. Indeed, the MO from these patients were the most efficient in the assay of antibody- and cellular-dependent inhibition of parasite multiplication (ADCI). These results support the hypothesis that discrete MO subpopulations are induced during malaria infection and are associated with anti-parasitic activity.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/_gpsXjh-LIE" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000631 Marcelo M. Samsa et al. info:doi/10.1371/journal.ppat.1000632 2009-10-23T07:00:00Z 2009-10-23T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Dengue virus is the single most significant arthropod-borne virus pathogen in humans. In spite of the urgent medical need to control dengue infections, vaccines are still unavailable, and many aspects of dengue virus biology and pathogenesis remain elusive. We discovered a link between dengue virus replication and ER-derived organelles known as lipid droplets (LDs). Dengue infection increases the amount of LDs per cell and pharmacological inhibition of LD formation greatly reduces dengue virus replication. In addition, we have found that the viral capsid protein in infected cells accumulates on the surface of LDs. Manipulation of infectious clones and generation of new reporter dengue viruses allowed us to define the molecular basis of capsid protein association to LDs. Specific amino acids on the α2 helix, located in the center of the capsid protein, were found to be crucial for both accumulation of capsid protein on LDs and dengue virus infectious particle formation. We propose that LDs facilitate viral replication providing a platform for nucleocapsid formation during encapsidation. Our findings begin to unravel the complex mechanism by which dengue virus usurps cellular organelles to coordinate different steps of the viral life cycle.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/9hGz07XTAvc" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000632 Dongyang Yu et al. info:doi/10.1371/journal.ppat.1000633 2009-10-23T07:00:00Z 2009-10-23T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">While receptor-mediated viral endocytosis or fusion with the cell membrane can be achieved through multiple surface molecules, the repetitious selection of two chemokine receptors, CCR5 or CXCR4, as the main HIV entry coreceptor implies an urgent viral need to exploit the chemotactic process in the immune system. Cytoskeletal rearrangement and cell migration are the primary consequences of chemotactic signaling. Nevertheless, previously published data demonstrated that depriving the virus of its signaling ability conferred higher infectivity through VSV-G-mediated endocytotic entry in transformed cells. We revisited the issue of chemokine coreceptor signaling and the role of cortical actin in HIV-1 latent infection of resting CD4 T cells, in which the virus can establish latency with a potential for productive replication upon T cell activation. Our results confirmed that only the genuine HIV-1 envelope protein, but not VSV-G, is capable of mediating latent infection of resting CD4 T cells. These findings highlight the importance of the HIV envelope and its signaling capacity in HIV infection of its natural target cells.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/TwL8baYvTV0" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000633 Sarah M. McDonald et al. info:doi/10.1371/journal.ppat.1000634 2009-10-23T07:00:00Z 2009-10-23T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Rotaviruses are the most important cause of severe diarrhea in infants and young children. Due to the segmented nature of their genomes, rotaviruses can exchange (reassort) genes during co-infections, a feature that is predicted to generate new, possibly more dangerous virus strains. However, the amount of gene reassortment occurring in nature is not known, as very few rotavirus genomes have been sequenced. To better understand the genetic make-up of rotaviruses circulating at a single location over a period of time, we sequenced the genomes of fifty-one isolates recovered from sick children from 1974 to 1991 at Children's Hospital National Medical Center, Washington, D. C. By analyzing these sequences, we found that several distinct groups (clades) of rotaviruses co-circulated and caused disease in a single epidemic season. In contrast to what was previously thought, very few rotaviruses exchanged gene segments with each other; instead, the genome constellations of the viruses remained relatively stable. We also discovered that these distinct rotavirus clades encode different viral proteins, which may be important in the development of effective vaccines. Together, the findings from this first large-scale rotavirus genomics project provide unparalleled insight into how these pathogens evolve during their spread through the human population.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/g3OhZODF8G8" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000634 Masmudur M. Rahman et al. info:doi/10.1371/journal.ppat.1000635 2009-10-23T07:00:00Z 2009-10-23T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Myxoma virus (MYXV), a rabbit-specific poxvirus pathogen, encodes diverse immunomodulatory proteins that can collectively overcome essentially all of the host immune defenses. MYXV-encoded protein M013, a member of the cellular PYRIN domain-containing superfamily of proteins, was previously shown to be important for virus virulence by blocking inflammasome regulated pro-inflammatory cytokine secretion. Here, we report that, in addition to targeting the ASC-1 protein of the host cell inflammasome complex, M013 also blocks activation of NF-κB signaling pathway by interacting with NF-κB1 and preventing nuclear translocation of the transcription factor RelA/p65. MYXV virus lacking a functional M013L gene (vMyxM013-KO) induced the early activation of NF-κB signaling pathway in human monocytic cells, causing the secretion of antiviral pro-inflammatory cytokines <i>in vitro</i> and <i>in vivo</i>. These results demonstrate that MYXV protein M013 is a multifunctional immunosubversive protein that co-regulates both the inflammasome complex and the NF-κB signaling pathway simultaneously.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/-Cb6glvcrFE" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000635 Jincun Zhao et al. info:doi/10.1371/journal.ppat.1000636 2009-10-23T07:00:00Z 2009-10-23T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Severe Acute Respiratory Syndrome (SARS) occurred in human populations in 2002–2003 and was caused by a novel coronavirus (CoV). Human SARS was characterized by prolonged virus excretion, lymphopenia and delayed adaptive immune responses in patients with severe disease. Recently, small animal models have been developed that mimic some of the features of the human disease. Specifically, BALB/c mice infected with mouse-adapted SARS-CoV develop severe respiratory disease. Here, we show that the T cell response is defective in these mice and that this results from inefficient activation of the initial immune response to the virus. This defect can be corrected by several treatments, including depletion of inhibitory macrophages from the lungs and direct activation of respiratory dendritic cells, important in initiating the immune response or transfer of activated dendritic cells prior to infection. All of these modalities result in improved initiation of the immune response and an enhanced anti-virus T cell response. Inefficient activation of the immune response may play a role in human SARS, and our results suggest possible strategies that might be used to develop novel anti-viral therapies.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/70VA-in79rY" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000636 Caroline B. Michielse et al. info:doi/10.1371/journal.ppat.1000637 2009-10-23T07:00:00Z 2009-10-23T07:00:00Z Author Summary <p xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:util="http://dtd.nlm.nih.gov/xsl/util" xmlns:fo="http://www.w3.org/1999/XSL/Format" xmlns:mml="http://www.w3.org/1998/Math/MathML">Plant pathogenic fungi have evolved many ways to infect their hosts and can have devastating effects on commercial crop production. Dissecting their infection strategies and understanding the molecular pathways involved in pathogenesis have been and continue to be the subject of intensive research. New insights gained may help to develop disease controlling strategies. <i>Fusarium oxysporum</i> has become a model for root invading, pathogenic fungi. This fungus attacks a wide range of plant species worldwide and the only effective disease control strategies in the field are crop rotation and usage of resistant plant varieties, if at all available. In the last decade, many genes have been identified that play a role during pathogenesis, many of which are linked to general strain fitness. Only few genes have been identified that are required for pathogenesis but do not affect vegetative growth. This paper describes the characterization of such a gene. Its protein product, Sge1, is conserved in the fungal kingdom and represents a new class of transcriptional regulators involved in morphological switching in dimorphic fungal pathogens. In <i>F. oxysporum</i>, the Sge1 protein is required for parasitic growth and is associated with expression of parasitic phase-specific genes. We suggest that the function of Sge1 is conserved in (plant) pathogenic fungi.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/aGcn9MkewY4" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000637