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 2009-11-09T06:04:08Z Subscribe with My Yahoo!Subscribe with NewsGatorSubscribe with My AOLSubscribe with BloglinesSubscribe with NetvibesSubscribe with GoogleSubscribe with Pageflakes 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 Christopher C. Kemball et al. info:doi/10.1371/journal.ppat.1000618 2009-10-16T07:00:00Z 2009-10-16T07:00:00Z 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 viruses—for example, large DNA viruses like smallpox virus and herpesviruses—encode several proteins whose major function is to combat the host's immune response, but these proteins usually battle in vain; in general, the mammalian immune system is sufficiently accomplished to penetrate this viral armor, allowing the infected animal to mount an immune response that can eradicate—or, at least, suppress—the infectious agent. Here, we show that coxsackievirus, a small RNA virus, carries a far more powerful punch than its larger DNA cousins; it almost entirely evades detection by host CD8⁺ T cells, which usually are one of the key components of an antiviral immune response. How does the virus achieve such success? Normally, when a virus infects a cell, certain host proteins capture small fragments of the virus and display them on the cell's surface, allowing them to be detected by the host immune system—usually, by cells called CD8⁺ T cells. We show here that coxsackievirus very effectively prevents these “flags” from reaching the cell surface in a form that can trigger naïve T cells to respond; in effect, the virus renders the cell “invisible” to CD8⁺ T cells, creating a cocoon in which the virus can multiply undisturbed by host immunity.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/Z5n0YV8AZG0" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000618 Michael A. Bachman et al. info:doi/10.1371/journal.ppat.1000622 2009-10-16T07:00:00Z 2009-10-16T07:00:00Z 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">Bacterial pathogens such as <i>Klebsiella pneumoniae</i> require iron and use secreted molecules called siderophores to strip iron from mammalian proteins. When bacteria colonize the upper respiratory tract, the mucosa secretes the protein lipocalin 2 (Lcn2) that binds to the siderophore enterobactin (Ent) and disrupts bacterial iron acquisition. In addition, Lcn2 bound to Ent stimulates release of the neutrophil-recruitment signal IL-8 from cultured respiratory cells. Some pathogens avoid Lcn2 binding by attaching glucose to Ent (to make Gly-Ent) or by making alternative siderophores. To determine the effect of Lcn2 on bacterial colonization, we colonized mice that express or lack Lcn2 with <i>K. pneumoniae</i> mutants that express or lack Ent, Gly-Ent and the alternative siderophore Yersiniabactin (Ybt). Our results indicate that mucosal Lcn2 inhibits colonization through iron sequestration and increases the influx of neutrophils in response to <i>K. pneumoniae</i> producing Ent. Therefore, Lcn2 acts as a barrier to colonization that pathogens must overcome to persist in the upper respiratory tract.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/JQENb-6lZNM" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000622 Evelyn Gassert et al. info:doi/10.1371/journal.ppat.1000623 2009-10-16T07:00:00Z 2009-10-16T07:00:00Z 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 ability of measles virus (MV) to impair T cell–dependent immune responses noted more than 100 years ago continues to be central to the severe generalised immunosuppression by this virus. Much has been learned about receptors and mechanisms, which determine the predilection of MV for hematopoetic cells. In contrast, little is known on a molecular level how MV interferes with processes relaying extracellular signals to T cells which translate into reorganisation of their cytoskeleton as required for their migration and cell–cell communication. Our study now shows that MV activates sphingomyelinases and ceramide accumulation in T cell membranes and this severely impairs integrity and stimulated reorganisation of their actin cytoskeleton, morphologically resulting in collapse of actin based protrusions, and functionally in impaired motility. During these studies, we appreciated, however, that cues other than MV eliciting ceramide accumulation in general also caused T cell paralysis. This indicates that ceramide accumulation and its consequences are not only a novel concept for MV-induced T cell silencing, but rather reflects a general strategy which may apply to extracellular ligands including pathogens able to promote plasma membrane ceramide accumulation, thereby preventing T cell activation.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/pJFVX6tyxlE" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000623 Feroz Sarkari et al. info:doi/10.1371/journal.ppat.1000624 2009-10-16T07:00:00Z 2009-10-16T07:00:00Z 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">Epstein-Barr virus (EBV) infections persist for the lifetime of the host largely due to the actions of the EBNA1 viral protein. EBNA1 enables the replication and stable persistence of EBV genomes and activates the expression of other EBV genes by binding to specific DNA sequences in the EBV genome. We have shown that the cellular protein USP7 stimulates EBNA1 binding to its DNA sequences and that EBNA1 recruits USP7 to the EBV genome, which in turn recruits another cellular protein GMP synthetase. The complex of USP7 and GMP synthetase then functions to alter the chromatin structure at a region of the EBV genome that controls EBV persistence. These changes to the EBV genome are likely important for enabling the persistence of EBV genomes in infected cells.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/rnx1Rywj1-Q" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000624 Sandra J. van Vliet et al. info:doi/10.1371/journal.ppat.1000625 2009-10-16T07:00:00Z 2009-10-16T07:00:00Z 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>Neisseria gonorrhoeae</i> is a species of Gram-negative bacteria responsible for the sexually transmitted disease gonorrhea. Although effective antibiotic treatments are available, little is known about the host immune response to this pathogen. Here, we analyzed three well-characterized gonococcal variants that only differ in the outer sugar present on the lipooligosaccharide of the bacteria. We found that human dendritic cells use different receptors, including the C-type lectins MGL and DC-SIGN, to detect the three <i>N. gonorrhoeae</i> phenotypes. Dendritic cells carrying the MGL and DC-SIGN receptor were present in the human genital tissues, the site of gonoccocal invasion. DC activation with the gonococcal variants resulted in different cytokine secretion profiles and alterations in the subsequent adaptive T cell response. In particular, LOS containing a terminal <i>N</i>-acetylgalactosamine induced more T helper 2-type responses, which are unfavorable for clearing the bacteria. Our data provide new insights into the pathogenesis of <i>N. gonorrhoeae</i> and suggest that variation of lipooligosaccharide glycosylation enables to bacteria to selectively subvert host immune defense mechanisms.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/SR_yJBeKKlo" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000625 Carsten Schwan et al. info:doi/10.1371/journal.ppat.1000626 2009-10-16T07:00:00Z 2009-10-16T07:00:00Z 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>Clostridium difficile</i> is responsible for ~20 percent of antibiotic-related cases of diarrhea and nearly all cases of pseudomembranous colitis. The pathogens produce two protein toxins (toxins A and B), which inactivate Rho-GTPases of host cells by glucosylation. Recently emerging hypervirulent strains of <i>C. difficile</i> release higher amounts of toxins A and B, are resistant towards fluoroquinolones and produce an additional protein toxin called <i>C. difficile</i> transferase (CDT). CDT is a binary toxin, which modifies G-actin by ADP-ribosylation, thereby inhibiting actin polymerization. So far the pathogenetic role of CDT is not clear. Here we studied the effects of CDT on human colon carcinoma cells and show that the toxin causes rearrangement of microtubules and formation of long cellular protrusions. The microtubule-based protrusions form a dense meshwork at the cell surface, which wrap and embed <i>Clostridia</i>, thereby increasing adherence of the pathogens. We observed similar effects with other members of the family of binary actin-ADP-ribosylating toxins like <i>C. botulinum</i> C2 toxin and <i>C. perfringens</i> iota toxin. Our findings show a novel type of microtubule structures induced by actin-ADP-ribosylating toxins and propose an important role of these toxins in host–pathogen interactions by their effects on adherence and colonization of <i>Clostridia</i>.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/-KHxtBcRhn8" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000626 Michael D. Moore et al. info:doi/10.1371/journal.ppat.1000627 2009-10-16T07:00:00Z 2009-10-16T07:00:00Z 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">High genetic diversity of HIV-1 presents a difficult barrier for drug treatment and vaccine development. HIV-1 efficiently reassorts mutations in its genome by packaging two copies of RNA into one virion and using portions of each RNA as the template for DNA synthesis. Thus, a key to HIV-1's genetic diversity is how it packages two RNAs into one virion. We have previously shown that HIV-1 packages RNA as a dimer, rather than two monomers. In this report, we determined that HIV-1 RNA finds its copackaged dimer partner mostly in the cytoplasm, not the nucleus, of the infected cells. We also found that the host cell machinery used to transport the HIV-1 RNA out of the nucleus affects the ability of two RNAs to copackage into one virion: HIV-1 RNAs transported using the CRM-1 pathway does not copackage efficiently with RNA transported by the NXF1 pathway. This is also the first demonstration that RNAs transported by the two major cellular pathways, CRM-1 and NXF1, are partially segregated at some point in the cytoplasm. Therefore, this work provides novel insights to both HIV replication mechanisms and cellular RNA transport pathways.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/saWLiREapL4" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000627 Adrien F. Vinet et al. info:doi/10.1371/journal.ppat.1000628 2009-10-16T07:00:00Z 2009-10-16T07:00:00Z 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">Upon their internalization by macrophages, <i>Leishmania donovani</i> promastigotes inhibit phagolysosome biogenesis. This inhibition is mediated by the virulence glycolipid lipophosphoglycan (LPG), attached to the promastigote surface. We recently showed that the exocytosis regulator Synaptotagmin (Syt) V controls early steps of phagocytosis, and remains associated to the phagosome during the maturation process. Here, we show that Syt V contributes to phagolysosome biogenesis by regulating the acquisition of the hydrolase cathepsin D and the vesicular proton-ATPase. Insertion of LPG into lipid microdomains of the phagosome membrane excluded Syt V from phagosomes, enabling <i>L. donovani</i> promatigotes to inhibit the recruitment of the vesicular proton-ATPase to phagosomes, preventing their acidification. Collectively, our results provide novel insight into the mechanism of vesicular proton-ATPase recruitment to maturing phagosomes and reveal how the virulence glycolipid LPG contributes to the mechanism of <i>L. donovani</i> pathogenesis by preventing phagosome acidification.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/V6UPzdammqQ" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000628 Xiaofei E et al. info:doi/10.1371/journal.ppat.1000609 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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">Autophagy (‘<i>self-eating</i>’, lysosome-dependent degradation and recycling of the intracellular components in response to stress) and apoptosis (‘<i>self-killing</i>’, cells commit suicide in response to stress) are important host defense mechanisms against viral infections. γ-herpesvirus 68 (γHV68) encodes a Bcl-2 family protein, vBcl-2, that effectively antagonizes both autophagy and apoptosis and is required for chronic viral infection and pathogenesis. However, the relative contributions of the vBcl-2-mediated evasion of autophagy and apoptosis to γHV68 persistent infection remain largely unknown. Here, we characterized a series of vBcl-2 mutants to genetically and functionally distinguish these closely related activities of vBcl-2 in vitro and in vivo. We have found that the inhibition of autophagy by vBcl-2 is important for maintaining latent infections, while the anti-apoptotic activity of vBcl-2 is largely involved in efficient viral reactivation from latency. Our findings thus reveal a novel paradigm for the vBcl-2-mediated evasion of autophagy and apoptosis during chronic viral infection, identifying a vital role for autophagy in controlling γHV68 latent infection.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/sE5jo4iOkPg" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000609 Fengwei Bai et al. info:doi/10.1371/journal.ppat.1000610 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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">West Nile virus (WNV), a mosquito-transmitted RNA virus, is a worldwide cause of severe human and animal infection. Mammalian host immune responses to WNV infection are not completely understood and a vaccine or specific therapy is unavailable for use in humans. In the present study, we investigated the putative regulatory role of interleukin-10 (IL-10) during WNV infection in mice. We found that IL-10 signaling facilitates WNV infection and suppresses antiviral cytokine production in response to viral infection. Interestingly, blockade of IL-10 signaling by IL-10 neutralizing antibody increases survival of WNV-infected mice, suggesting a potentially novel therapeutic strategy to combat WNV infection. In addition, we found that CD4⁺ T cells produce a significant amount of IL-10 during WNV infection, providing a more accurate cellular target for IL-10 signaling inhibition. IL-10 also plays a critical role in suppression of excessive inflammation and immunopathology caused by autoimmune diseases or host immune system responses to infections; therefore, safety and efficacy of IL-10 signaling blockade as a therapeutic strategy against WNV infection deserves consideration.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/hXNEhawBxXI" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000610 Michael J. Smout et al. info:doi/10.1371/journal.ppat.1000611 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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 oriental liver fluke is endemic through South-East Asia and is the major cause of cause of liver cancer in north-eastern Thailand. The molecules that are secreted by the parasite cause cells to multiply quicker than they normally would, and excessive cell growth is a key stage in the initiation of many cancers. We identified a secreted protein from the fluke, termed granulin, which has a similar structure to a human growth factor associated with many aggressive cancers. Granulin is secreted by the parasite into the bile ducts where it causes host cells to proliferate. The proliferative activity of fluke secreted proteins was blocked by antibodies against granulin, indicating that it is the major cell growth-inducing molecule released by the parasite. Identifying the function of granulin will enable us to understand how and why this debilitating yet neglected pathogen causes cancer in so many people in South-East Asia. This and future work will contribute towards the development of new strategies to reduce both parasite prevalence and the incidence of the most fatal of liver cancers in Thailand.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/7AIOzmQJwEw" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000611 Christopher Askew et al. info:doi/10.1371/journal.ppat.1000612 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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">Pathogens must be able to assimilate the carbon sources in their environment to generate sufficient energy and metabolites to survive. Since glycolysis is a central metabolic pathway, it is important for this metabolic flexibility. The most commonly isolated agent in human fungal infections, <i>Candida albicans</i>, depends upon glycolysis for the progression of systemic disease. We investigated glycolytic transcriptional regulation in <i>C. albicans</i> and defined two key regulators of the pathway, Tye7p and Gal4p. We demonstrated that these factors are important for the fermentative growth of <i>C. albicans</i> both <i>in vitro</i> and <i>in vivo</i> and also regulate the input and output fluxes of glycolysis. The <i>gal4tye7</i> strain showed attenuated virulence in a <i>Galleria</i> and two mouse models, potentially due to the severe growth defect in oxygen-limiting environments. Gal4p and Tye7p represent fungal specific regulators involved in the pathogenicity of the organism that may be exploited in the development of antifungal treatments. Our study describes a fungal glycolytic transcriptional circuit that is fundamentally different from that of the model yeast <i>Saccharomyces cerevisiae</i>, providing further evidence that the transcriptional networks in <i>S. cerevisiae</i> need not be generally representative of the fungal kingdom.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/9BiT0LgXtjY" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000612 Kathryn C. Meier et al. info:doi/10.1371/journal.ppat.1000614 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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 highly lethal viral hemorrhagic fever caused by the mosquito-borne yellow fever virus (YFV) affects hundreds of thousands of people annually, despite the availability of the live-attenuated 17D vaccine, developed in the 1930s by serial passage of wild-type strain Asibi. Our understanding of the molecular mechanisms controlling YFV virulence and pathogenesis, and attenuation of the 17D vaccine virus, is limited, with progress greatly impeded by the lack of a small animal model reproducing human disease. Here, we demonstrate that the wild-type Asibi virus and 17D-204 vaccine substrain are readily distinguishable on the basis of morbidity, mortality and pathogenesis when inoculated subcutaneously into mice with deficiencies in their type I interferon (IFN-α/β) antiviral response. In these animals, Asibi virus infection exhibits pronounced viscerotropism, causing severe histopathology in liver and spleen, correlated with dysregulated cytokine induction, emulating hallmark features of human YF. Importantly, 17D-204 virus infection of these mice is rapidly self-limiting and subclinical as in human vaccinees. This newly developed YF disease model can be exploited to identify determinants of YFV virulence and reveal molecular mechanisms that control the virus/host interaction, providing a framework for rational design of acute phase therapeutics and improved vaccines for protection against YFV and other flaviviruses.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/e-n0ZpH2l2I" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000614 Anette Rejman Lipinski et al. info:doi/10.1371/journal.ppat.1000615 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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>Chlamydia trachomatis</i> is the leading cause of sexually transmitted disease and preventable blindness in humans. These bacteria survive and replicate within a membrane bound niche inside host cells, termed the inclusion. The inclusion expands as <i>Chlamydia</i> replicate, likely fuelled by the interception of cellular trafficking pathways to acquire essential nutrients. Certain host proteins, the Rab GTPases, have previously been observed at inclusion membranes, but the function of this host–pathogen interaction remains unknown. Here, we show distinct Rab proteins are important for the outcome of an infection. Depletion of Rab6 and Rab11 by RNA interference inhibited <i>Chlamydia</i>-induced fragmentation of the Golgi apparatus (GA), a key organelle functioning in the processing and packaging of cell synthesized macromolecules, accompanied by a decrease in bacterial progeny and a reduction in lipid transport to the inclusion. Our investigation of the cross-talk between <i>Chlamydia</i> and a host cell trafficking pathway not only further strengthens our group's previous finding that <i>Chlamydia</i> subverts GA structure to enhance replication, but has identified Rab6 and Rab11 as key regulators of GA stability. In the wider context, our results also raise the provocative notion of a novel anti-chlamydial treatment based on interference with GA function.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/nHn8eEJAwVY" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000615 Victoria Emuss et al. info:doi/10.1371/journal.ppat.1000616 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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">Kaposi sarcoma herpesvirus (KSHV) is a tumour virus associated with Kaposi sarcoma (KS). Most KS tumor cells are latently infected with the virus, while a small number are lytically infected and produce KSHV. The Notch signaling pathway is highly conserved and important in development and disease. Classical activation of this pathway occurs through direct interaction between ligands and receptors bound to the surface of adjacent cells and influences gene expression in cells receiving the signal. KS tumour cells express Notch pathway components and are sensitive to inhibition of Notch signaling, suggesting this pathway may be important in the development of KS; however, no mechanism behind the classical activation of Notch by KSHV has been established. We describe the molecular mechanisms through which KSHV hijacks the Notch signaling pathway by directly increasing the expression of two Notch ligands (JAG1 and DLL4) through two KSHV genes expressed during latent and lytic infection, respectively. We show the effect of JAG1- and DLL4-stimulated signaling on gene expression in adjacent cells and show that both ligands affect cell cycle-associated genes and may co-operate to permit functional signaling in the context of both latent and lytic infection.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/eog6-lhPWnY" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000616 Sara K. Lindén et al. info:doi/10.1371/journal.ppat.1000617 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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 bacterium <i>Helicobacter pylori</i> can cause peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma. <i>H. pylori</i> colonize the mucosal surface of the stomach, where adherence helps the bacteria to remain in the neutral and protected niche under the mucus layer, and helps it withstand the continuous mucus washing of the mucosal surface. Adherence is also thought to mediate much of the <i>H. pylori</i> mediated disease. The cell-surface mucin MUC1 is highly expressed on the mucosal surface and limits the density of <i>H. pylori</i> in a murine infection model. We now demonstrate that the majority of <i>H. pylori</i> strains can bind to human MUC1 and that release of MUC1 following binding limits adhesion to the cell surface. Furthermore, MUC1 protects the epithelium from non-MUC1 binding bacteria by acting as a physical barrier to adhesion to other cell surface molecules. Thus, appropriate expression and function of MUC1 is likely to limit development of disease ensuing from chronic <i>H. pylori</i> infection.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/gasyu5WFWMk" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000617 Christine M. Livingston et al. info:doi/10.1371/journal.ppat.1000619 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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">Protein quality control is a protective cellular mechanism by which damaged proteins are refolded or degraded so that they cannot interfere with essential cellular processes. In the event that protein quality control machinery cannot refold or degrade damaged proteins, sequestration of misfolded protein is an alternative protective mechanism for reducing the toxic effects of misfolded protein. Several neurological diseases result from the accumulation of toxic misfolded proteins that cannot be efficiently refolded or degraded. In neurons from patients afflicted with Huntington's disease, misfolded huntingtin protein is sequestered in large aggregates in the nucleus called inclusion bodies. Inclusion bodies also contain protein quality control machinery including molecular chaperones, the proteasome and ubiquitin. Here we report that analogous structures called Virus-Induced Chaperone-Enriched (VICE) domains form in the nucleus of cells infected with Herpes Simplex Virus type 1 (HSV-1). VICE domains contain misfolded protein, chaperones and protein degradation activity. VICE domain formation is efficient in infected cells taxed with high levels of viral protein production. We hypothesize that misfolded proteins that arise in HSV-1-infected cells are sequestered in VICE domains to promote remodeling of misfolded proteins.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/P81wGg-XOhQ" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000619 Tobias J. Tuthill et al. info:doi/10.1371/journal.ppat.1000620 2009-10-09T07:00:00Z 2009-10-09T07:00:00Z 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">Picornaviruses are small animal viruses comprising an RNA genome protected by a roughly spherical protein shell with icosahedral symmetry. How the RNA is introduced into the cytoplasm of the host cell to initiate replication is unclear since they have no lipid envelope to facilitate fusion with cellular membranes. Instead, they become internalized into endocytic vesicles whence the viral genome must be delivered through the vesicle membrane, into the cytoplasm. In some picornaviruses (enteroviruses), genome delivery is proposed to be coordinated by an intact particle inducing pore formation in the membrane through which the genome can be transferred directly without exposure to the hostile vesicle environment. In contrast, other picornaviruses (aphthoviruses e.g. ERAV, FMDV) present a dilemma by appearing to simply fall apart in acidified vesicles. Here we show that acid treatment results in the formation of an intact but transient aphthovirus empty particle from which the genome has been released. We have determined the crystal structures of the ERAV particle at native and acidic pH. The acid induced structure is consistent with a destabilized particle en-route to disassembly. We propose that the entry process for this group of viruses involves externalisation of the RNA from a novel capsid intermediate and unifies in principle the entry process for all picornaviruses.</p><img src="http://feeds.feedburner.com/~r/plospathogens/NewArticles/~4/gTcX5mUZf94" height="1" width="1"/> http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000620