PLoS Pathogens

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ISSN / EISSN : 15537366 / 15537374
Current Publisher: Public Library of Science (PLoS) (10.1371)
Total articles ≅ 8,170
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Sarah L. Caddy, Marina Vaysburd, Mark Wing, Stian Foss, Jan Terje Andersen, Kevin O‘Connell, Keith Mayes, Katie Higginson, Miren Iturriza-Gómara, Ulrich Desselberger, et al.
PLOS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008732

Abstract:
Rotavirus is a major cause of gastroenteritis in children, with infection typically inducing high levels of protective antibodies. Antibodies targeting the middle capsid protein VP6 are particularly abundant, and as VP6 is only exposed inside cells, neutralisation must be post-entry. However, while a system of poly immune globulin receptor (pIgR) transcytosis has been proposed for anti-VP6 IgAs, the mechanism by which VP6-specific IgG mediates protection remains less clear. We have developed an intracellular neutralisation assay to examine how antibodies neutralise rotavirus inside cells, enabling comparison between IgG and IgA isotypes. Unexpectedly we found that neutralisation by VP6-specific IgG was much more efficient than by VP6-specific IgA. This observation was highly dependent on the activity of the cytosolic antibody receptor TRIM21 and was confirmed using an in vivo model of murine rotavirus infection. Furthermore, mice deficient in only IgG and not other antibody isotypes had a serious deficit in intracellular antibody-mediated protection. The finding that VP6-specific IgG protect mice against rotavirus infection has important implications for rotavirus vaccination. Current assays determine protection in humans predominantly by measuring rotavirus-specific IgA titres. Measurements of VP6-specific IgG may add to existing mechanistic correlates of protection. Rotavirus is the leading cause of gastroenteritis in children worldwide. Effective rotavirus vaccines have been available for over a decade, but detailed understanding of the immune response to rotavirus infection is essential for further improvement of vaccines. High levels of antibodies are made in response to infection, especially antibodies targeting the inner capsid protein VP6, but while both IgA and IgG isotypes are produced, previous work has focused predominantly on VP6-specific IgA. In this study we sought to evaluate the importance of VP6-specific IgG in rotavirus protection. As VP6-specific antibodies target incomplete rotavirus particles inside cells, we developed a new assay to examine how antibodies neutralise rotavirus intracellularly. We showed that neutralisation by VP6-specific IgG was much more efficient than VP6-specific IgA, due to the activity of the cytosolic antibody receptor TRIM21. This was confirmed using a mouse model of rotavirus infection. Furthermore, mice with normal IgA levels but deficient in IgG had a serious deficit in intracellular antibody-mediated protection. Our finding that VP6-specific IgG protect mice against rotavirus infection may be valuable for predicting whether new rotavirus vaccines will work. Current assays to determine protection in humans focus on measuring rotavirus-specific IgA titres. We propose that including measurements of VP6-specific IgG may improve knowledge on correlates of protection.
Brendan D. Snarr, Guillaume St-Pierre, Benjamin Ralph, Mélanie Lehoux, Yukiko Sato, Ann Rancourt, Takahiro Takazono, Shane R. Baistrocchi, Rachel Corsini, Matthew P. Cheng, et al.
PLoS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008741

Abstract:
Aspergillus fumigatus is an opportunistic mold that infects patients who are immunocompromised or have chronic lung disease, causing significant morbidity and mortality in these populations. While the factors governing the host response to A. fumigatus remain poorly defined, neutrophil recruitment to the site of infection is critical to clear the fungus. Galectin-3 is a mammalian β-galactose-binding lectin with both antimicrobial and immunomodulatory activities, however the role of galectin-3 in the defense against molds has not been studied. Here we show that galectin-3 expression is markedly up-regulated in mice and humans with pulmonary aspergillosis. Galectin-3 deficient mice displayed increased fungal burden and higher mortality during pulmonary infection. In contrast to previous reports with pathogenic yeast, galectin-3 exhibited no antifungal activity against A. fumigatus in vitro. Galectin-3 deficient mice exhibited fewer neutrophils in their airways during infection, despite normal numbers of total lung neutrophils. Intravital imaging studies confirmed that galectin-3 was required for normal neutrophil migration to the airspaces during fungal infection. Adoptive transfer experiments demonstrated that stromal rather than neutrophil-intrinsic galectin-3 was necessary for normal neutrophil entry into the airspaces. Live cell imaging studies revealed that extracellular galectin-3 directly increases neutrophil motility. Taken together, these data demonstrate that extracellular galectin-3 facilitates recruitment of neutrophils to the site of A. fumigatus infection, and reveals a novel role for galectin-3 in host defense against fungal infections. The environmental mold Aspergillus fumigatus commonly causes lung infections in people with impaired immunity or those suffering from a chronic lung disease. While neutrophils are a key cell type necessary for the eradication of this infection, the precise mechanism of their recruitment to the site of infection remains incompletely understood. Here we show that the secreted mammalian protein galectin-3 plays an important role in helping neutrophils reaching the fungus within the airways. We found that both mice and humans produce galectin-3 when infected with A. fumigatus, and mice lacking galectin-3 were more susceptible to infection than normal mice. Galectin-3-deficient mice had impaired neutrophil recruitment to the site of infection. In the absence of galectin-3, neutrophils exhibited reduced motility in mouse lungs and in tissue culture. Our study offers insights into the mechanisms underlying the recruitment of neutrophils to the airways during A. fumigatus infection and reveals a new role for galectin-3 in increasing neutrophil motility.
Timothy M. Tucey, Jiyoti Verma, Françios A. B. Olivier, Tricia L. Lo, Avril A. B. Robertson, Thomas Naderer, Ana Traven
PLoS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008695

Abstract:
The NLRP3 inflammasome has emerged as a central immune regulator for sensing virulence factors expressed by microbial pathogens for triggering antimicrobial inflammation. Inflammation can be harmful and therefore this response must be tightly controlled. The mechanisms by which immune cells, such as macrophages, discriminate benign from pathogenic microbes to control the NLRP3 inflammasome remain poorly defined. Here we used live cell imaging coupled with a compendium of diverse clinical isolates to define how macrophages respond and activate NLRP3 when faced with the human yeast commensal and pathogen Candida albicans. We show that metabolic competition by C. albicans, rather than virulence traits such as hyphal formation, activates NLRP3 in macrophages. Inflammasome activation is triggered by glucose starvation in macrophages, which occurs when fungal load increases sufficiently to outcompete macrophages for glucose. Consistently, reducing Candida’s ability to compete for glucose or increasing glucose availability for macrophages tames inflammatory responses. We define the mechanistic requirements for glucose starvation-dependent inflammasome activation by Candida and show that it leads to inflammatory cytokine production, but it does not trigger pyroptotic macrophage death. Pyroptosis occurs only with some clinical Candida isolates and only under specific experimental conditions, whereas inflammasome activation by glucose starvation is broadly relevant. In conclusion, macrophages use their metabolic status, specifically glucose metabolism, to sense fungal metabolic activity and increased microbial loads for activating NLRP3. Therefore, a major consequence of Candida-induced glucose starvation in macrophages is activation of inflammatory responses, with implications for understanding how metabolism modulates inflammation in fungal infections. Activation of the immune regulator NLRP3 inflammasome by microbial pathogens has been shown to play both protective and destructive roles in infection, underscoring the importance of tight control over NLRP3-driven inflammation to ensure host health. A key microbe recognised by NLRP3 is the human yeast commensal and pathogen Candida albicans, which is responsible for mucosal and invasive infections. We demonstrate that innate immune cells sense their metabolic status to trigger NLRP3 activation only when microbial numbers have reached dangerous levels. This regulation is a consequence of metabolic competition between C. albicans and macrophages for an essential nutrient–glucose. The NLRP3 inflammasome is activated when increased fungal load in the infection microenvironment drives down glucose levels, thereby causing glucose starvation in macrophages. Restoring glucose homeostasis in macrophages reduced NLRP3 activation and production of the proinflammatory cytokine IL-1β, suggesting that metabolism regulates NLRP3 inflammasome activity in fungal infections.
John H.-O. Pettersson, Patrik Ellström, Jiaxin Ling, Ingela Nilsson, Sven Bergström, Daniel González-Acuña, Björn Olsen, Edward C. Holmes
PLOS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008759

Abstract:
Ticks (order: Ixodida) are a highly diverse and ecologically important group of ectoparasitic blood-feeding organisms. One such species, the seabird tick (Ixodes uriae), is widely distributed around the circumpolar regions of the northern and southern hemispheres. It has been suggested that Ix. uriae spread from the southern to the northern circumpolar region millions of years ago and has remained isolated in these regions ever since. Such a profound biographic subdivision provides a unique opportunity to determine whether viruses associated with ticks exhibit the same evolutionary patterns as their hosts. To test this, we collected Ix. uriae specimens near a Gentoo penguin (Pygoscelis papua) colony at Neko harbour, Antarctica, and from migratory birds—the Razorbill (Alca torda) and the Common murre (Uria aalge)—on Bonden island, northern Sweden. Through meta-transcriptomic next-generation sequencing we identified 16 RNA viruses, seven of which were novel. Notably, we detected the same species, Ronne virus, and two closely related species, Bonden virus and Piguzov virus, in both hemispheres indicating that there have been at least two cross-circumpolar dispersal events. Similarly, we identified viruses discovered previously in other locations several decades ago, including Gadgets Gully virus, Taggert virus and Okhotskiy virus. By identifying the same or closely related viruses in geographically disjunct sampling locations we provide evidence for virus dispersal within and between the circumpolar regions. In marked contrast, our phylogenetic analysis revealed no movement of the Ix. uriae tick hosts between the same locations. Combined, these data suggest that migratory birds are responsible for the movement of viruses at both local and global scales. As host populations diverge, so may those microorganisms, including viruses, that are dependent on those hosts. To examine this key issue in host-microbe evolution we compared the co-phylogenies of the seabird tick, Ixodes uriae, and their RNA viruses sampled from the far northern and southern hemispheres. Despite the huge geographic distance between them, phylogeographic analysis reveals that the same and closely related viruses were found both within and between the northern and southern circumpolar regions, most likely reflecting transfer by virus-infected migratory birds. In contrast, genomic data suggested that the Ix. uriae populations were phylogenetically distinct between the northern and southern hemispheres. This work emphasises the importance of migratory birds and ticks as vectors and sources of virus dispersal and introduction at both the local and global scales.
Katherine S. Forsyth, Nathan H. Roy, Elise Peauroi, Brian C. DeHaven, Erik D. Wold, Adam R. Hersperger, Janis K Burkhardt, Laurence C. Eisenlohr
PLoS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008685

Abstract:
Smallpox and monkeypox pose severe threats to human health. Other orthopoxviruses are comparably virulent in their natural hosts, including ectromelia, the cause of mousepox. Disease severity is linked to an array of immunomodulatory proteins including the B22 family, which has homologs in all pathogenic orthopoxviruses but not attenuated vaccine strains. We demonstrate that the ectromelia B22 member, C15, is necessary and sufficient for selective inhibition of CD4+ but not CD8+ T cell activation by immunogenic peptide and superantigen. Inhibition is achieved not by down-regulation of surface MHC- II or co-stimulatory protein surface expression but rather by interference with antigen presentation. The appreciable outcome is interference with CD4+ T cell synapse formation as determined by imaging studies and lipid raft disruption. Consequently, CD4+ T cell activating stimulus shifts to uninfected antigen-presenting cells that have received antigen from infected cells. This work provides insight into the immunomodulatory strategies of orthopoxviruses by elucidating a mechanism for specific targeting of CD4+ T cell activation, reflecting the importance of this cell type in control of the virus. Orthopoxviruses pose considerable threats to their hosts by producing a battery of proteins that disable the immune system at many levels through mechanisms that remain poorly understood. An essential part of most immune responses is the activation of CD4+ T cells by antigen-presenting cells through formation of a supramolecular structure termed the immunological synapse. We show here that the C15 protein of ectromelia, the cause of mousepox, inhibits CD4+ T cell activation through a novel immunoevasion mechanism that results in disruption of synapse formation. As many poxviruses encode C15 homologs, these studies could provide insights into the virulence of other family members including monkeypox and smallpox, both of great concern to human populations.
Eerik Aunin, Ulrike Böhme, Theo Sanderson, Noah D. Simons, Tony L. Goldberg, Nelson Ting, Colin A. Chapman, Chris I. Newbold, Matthew Berriman, Adam J. Reid
PLoS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008717

Abstract:
Hepatocystis is a genus of single-celled parasites infecting, amongst other hosts, monkeys, bats and squirrels. Although thought to have descended from malaria parasites (Plasmodium spp.), Hepatocystis spp. are thought not to undergo replication in the blood–the part of the Plasmodium life cycle which causes the symptoms of malaria. Furthermore, Hepatocystis is transmitted by biting midges, not mosquitoes. Comparative genomics of Hepatocystis and Plasmodium species therefore presents an opportunity to better understand some of the most important aspects of malaria parasite biology. We were able to generate a draft genome for Hepatocystis sp. using DNA sequencing reads from the blood of a naturally infected red colobus monkey. We provide robust phylogenetic support for Hepatocystis sp. as a sister group to Plasmodium parasites infecting rodents. We show transcriptomic support for a lack of replication in the blood and genomic support for a complete loss of a family of genes involved in red blood cell invasion. Our analyses highlight the rapid evolution of genes involved in parasite vector stages, revealing genes that may be critical for interactions between malaria parasites and mosquitoes. Hepatocystis parasites are single-celled organisms, closely related to the Plasmodium species which cause malaria. But Hepatocystis are distinct–unlike Plasmodium they are thought not to replicate in the blood and cause little or no disease in their mammalian hosts. They are transmitted from one host to the next, not by mosquitoes, but by biting midges. In this study we generated a genome sequence for Hepatocystis–the first time this data has ever been produced and analysed for this species. We compared genome sequences of Hepatocystis and Plasmodium, confirming that Hepatocystis is descended from Plasmodium. We strengthened support for the absence of replication in the blood and, in line with this finding, discovered that genes involved in interaction with red blood cells have been lost in Hepatocystis. Our analyses revealed rapid evolution of genes which are active when the parasite is in the insect vector, highlighting those which might be important for understanding interaction between malaria parasites and mosquitoes. Hepatocystis has a fascinating evolutionary story and is a powerful comparator for understanding malaria parasite biology.
Xiaohua Ye, Hang Su, Daniel Wrapp, Daniel C. Freed, Fengsheng Li, Zihao Yuan, Aimin Tang, Leike Li, Zhiqiang Ku, Wei Xiong, et al.
PLoS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008736

Abstract:
Human cytomegalovirus (HCMV) is one of the main causative agents of congenital viral infection in neonates. HCMV infection also causes serious morbidity and mortality among organ transplant patients. Glycoprotein B (gB) is a major target for HCMV neutralizing antibodies, yet the underlying neutralization mechanisms remain largely unknown. Here we report that 3–25, a gB-specific monoclonal antibody previously isolated from a healthy HCMV-positive donor, efficiently neutralized 14 HCMV strains in both ARPE-19 cells and MRC-5 cells. The core epitope of 3–25 was mapped to a highly conserved linear epitope on antigenic domain 2 (AD-2) of gB. A 1.8 Å crystal structure of 3–25 Fab in complex with the peptide epitope revealed the molecular determinants of 3–25 binding to gB at atomic resolution. Negative-staining electron microscopy (EM) 3D reconstruction of 3–25 Fab in complex with de-glycosylated postfusion gB showed that 3–25 Fab fully occupied the gB trimer at the N-terminus with flexible binding angles. Functionally, 3–25 efficiently inhibited HCMV infection at a post-attachment step by interfering with viral membrane fusion, and restricted post-infection viral spreading in ARPE-19 cells. Interestingly, bivalency was required for HCMV neutralization by AD-2 specific antibody 3–25 but not the AD-4 specific antibody LJP538. In contrast, bivalency was not required for HCMV binding by both antibodies. Taken together, our results reveal the structural basis of gB recognition by 3–25 and demonstrate that inhibition of viral membrane fusion and a requirement of bivalency may be common for gB AD-2 specific neutralizing antibody. HCMV infection is usually asymptomatic in healthy individuals. However, life-threatening diseases frequently accompany HCMV infection in individuals with under-developed or compromised immune systems. Glycoprotein B antigenic domain 2 (AD-2) is a major target for HCMV-neutralizing antibodies that potentially provide immune protection. We report the structure-based study of gB recognition by a potent neutralizing antibody named 3–25 that binds a highly conserved epitope on AD-2. Functionally, 3–25 efficiently inhibited HCMV infection at a post-attachment step by interfering with viral membrane fusion, and restricted post-infection viral spreading. Furthermore, bivalency of 3–25 is required for viral neutralization but not for binding. Our findings advance understanding of gB antibody-mediated HCMV neutralization and facilitate development of gB-targeted vaccines and antibody drugs against HCMV infection.
Shuai Liu, Zhangmengxue Lei, Jie Li, Liu Wang, Ran Jia, Zhongshun Liu, Congwei Jiang, Ying Gao, Mu Liu, Linlin Kuang, et al.
PLoS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008701

Abstract:
Gammaherpesviruses have evolved various strategies to take advantage of host cellular factors or signaling pathways to establish a lifelong latent infection. Like the human gammaherpesvirus Epstein-Barr virus, murine gammaherpesvirus 68 (MHV68) establishes and maintains latency in the memory B cells during infection of laboratory mice. We have previously shown that MHV68 can immortalize fetal liver-derived B cells that induce lymphomas when injected into immunodeficient mice. Here we identify interleukin 16 (IL16) as a most abundantly expressed cytokine in MHV68-immortalized B cells and show that MHV68 infection elevates IL16 expression. IL16 is not important for MHV68 lytic infection but plays a critical role in MHV68 reactivation from latency. IL16 deficiency increases MHV68 lytic gene expression in MHV68-immortalized B cells and enhances reactivation from splenic latency. Correlatively, IL16 deficiency increases the frequency of MHV68-infected plasma cells that can be attributed to enhanced MHV68 reactivation. Furthermore, similar to TPA-mediated lytic replication of Kaposi's sarcoma-associated herpesvirus, IL16 deficiency markedly induces Tyr705 STAT3 de-phosphorylation and elevates p21 expression, which can be counteracted by the tyrosine phosphatase inhibitor orthovanadate. Importantly, orthovanadate strongly blocks MHV68 lytic gene expression mediated by IL16 deficiency. These data demonstrate that virus-induced IL16 do not directly participate in MHV68 lytic replication, but rather inhibits virus reactivation to facilitate latent infection, in part through the STAT3-p21 axis. Gammaherpesviruses establish life-long infection in B cells through the regulation of virus-host interaction. Following initial lytic infection, viruses infect B cells and take advantage of host cellular factors and signaling pathways to manipulate B cell responses, ultimately establish latency in B cells, which can be reactivated to induce lytic replication in some circumstances. Here we use a mouse model of gammaherpesvirus infection and show that IL16, one unique cytokine regulating CD4+ T cell function, is highly abundant in gammaherpesvirus-associated lymphoma cells and can be induced by gammaherpesvirus infection. In the absence of IL16, virus reactivation from B cells is markedly enhanced and the frequency of virus-infected plasma cells that account for virus reactivation is also significantly increased. These results illustrate how gammaherpesvirus take advantage of host cellular factor to regulate its life-long latent infection.
Zhihao Jiang, Kun Zhang, Zhaolei Li, Zhenggang Li, Meng Yang, Xuejiao Jin, Qing Cao, Xueting Wang, Ning Yue, Dawei Li, et al.
PLoS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008709

Abstract:
Nine genera of viruses in five different families use triple gene block (TGB) proteins for virus movement. The TGB modules fall into two classes: hordei-like and potex-like. Although TGB-mediated viral movement has been extensively studied, determination of the constituents of the viral ribonucleoprotein (vRNP) movement complexes and the mechanisms underlying their involvement in vRNP-mediated movement are far from complete. In the current study, immunoprecipitation of TGB1 protein complexes formed during Barley stripe mosaic virus (BSMV) infection revealed the presence of the γb protein in the products. Further experiments demonstrated that TGB1 interacts with γb in vitro and in vivo, and that γb-TGB1 localizes at the periphery of chloroplasts and plasmodesmata (PD). Subcellular localization analyses of the γb protein in Nicotiana benthamiana epidermal cells indicated that in addition to chloroplast localization, γb also targets the ER, actin filaments and PD at different stages of viral infection. By tracking γb localization during BSMV infection, we demonstrated that γb is required for efficient cell-to-cell movement. The N-terminus of γb interacts with the TGB1 ATPase/helicase domain and enhances ATPase activity of the domain. Inactivation of the TGB1 ATPase activity also significantly impaired PD targeting. In vitro translation together with co-immunoprecipitation (co-IP) analyses revealed that TGB1-TGB3-TGB2 complex formation is enhanced by ATP hydrolysis. The γb protein positively regulates complex formation in the presence of ATP, suggesting that γb has a novel role in BSMV cell-to-cell movement by directly promoting TGB1 ATPase-mediated vRNP movement complex assembly. We further demonstrated that elimination of ATPase activity abrogates PD and actin targeting of Potato virus X (PVX) and Beet necrotic yellow vein virus (BNYVV) TGB1 proteins. These results expand our understanding of the multifunctional roles of γb and provide new insight into the functions of TGB1 ATPase domains in the movement of TGB-encoding viruses. Plant viruses employ varied movement strategies to mediate local and systemic infections. Viral ribonucleoprotein (vRNP) movement complexes comprising either the hordei- or potex-like triple gene block (TGB) and viral RNAs represent important models for plant virus movement. However, the constituents of viral ribonucleoprotein (vRNP) movement complexes as well as their biological significance in vRNP assembly and subsequent interactions are far from complete. Additionally, the mechanistic roles of the highly conserved TGB1 ATPase domain in vRNP-mediated movement remain an enigma. Here, we demonstrate that the γb protein acts as a novel positive regulator of BSMV cell-to-cell movement by directly interacting with the TGB1 protein. In vitro biochemical assays verified an essential role of TGB1 ATPase-mediated ATP hydrolysis in assembly of vRNP movement complexes, a process that can be further enhanced by the γb protein. We also extend our studies of BSMV TGB1 ATPase to those of PVX and BNYVV, and suggest a model for an evolutionally conserved mode of energy-coupled vRNP movement complex assembly among different TGB-encoding viruses. Our results address the knowledge gap between TGB1 ATPase activity and vRNP movement complex assembly and expand our understanding of the multifaceted roles of γb in BSMV infection.
Andrew M. Borman, Elizabeth M. Johnson
PLOS Pathogens, Volume 16; doi:10.1371/journal.ppat.1008563

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