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PLoS Pathogens

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https://www.readbyqxmd.com/read/28542603/a-conformational-switch-high-throughput-screening-assay-and-allosteric-inhibition-of-the-flavivirus-ns2b-ns3-protease
#1
Matthew Brecher, Zhong Li, Binbin Liu, Jing Zhang, Cheri A Koetzner, Adham Alifarag, Susan A Jones, Qishan Lin, Laura D Kramer, Hongmin Li
The flavivirus genome encodes a single polyprotein precursor requiring multiple cleavages by host and viral proteases in order to produce the individual proteins that constitute an infectious virion. Previous studies have revealed that the NS2B cofactor of the viral NS2B-NS3 heterocomplex protease displays a conformational dynamic between active and inactive states. Here, we developed a conformational switch assay based on split luciferase complementation (SLC) to monitor the conformational change of NS2B and to characterize candidate allosteric inhibitors...
May 25, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542620/elevated-catalase-expression-in-a-fungal-pathogen-is-a-double-edged-sword-of-iron
#2
Arnab Pradhan, Carmen Herrero-de-Dios, Rodrigo Belmonte, Susan Budge, Angela Lopez Garcia, Aljona Kolmogorova, Keunsook K Lee, Brennan D Martin, Antonio Ribeiro, Attila Bebes, Raif Yuecel, Neil A R Gow, Carol A Munro, Donna M MacCallum, Janet Quinn, Alistair J P Brown
Most fungal pathogens of humans display robust protective oxidative stress responses that contribute to their pathogenicity. The induction of enzymes that detoxify reactive oxygen species (ROS) is an essential component of these responses. We showed previously that ectopic expression of the heme-containing catalase enzyme in Candida albicans enhances resistance to oxidative stress, combinatorial oxidative plus cationic stress, and phagocytic killing. Clearly ectopic catalase expression confers fitness advantages in the presence of stress, and therefore in this study we tested whether it enhances fitness in the absence of stress...
May 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542613/suppression-of-il-12p70-formation-by-il-2-or-following-macrophage-depletion-causes-t-cell-autoreactivity-leading-to-cns-demyelination-in-hsv-1-infected-mice
#3
Dhong Hyun Lee, Mandana Zandian, Jane Kuo, Kevin R Mott, Shuang Chen, Moshe Arditi, Homayon Ghiasi
We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1...
May 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542595/antifungal-tc17-cells-are-durable-and-stable-persisting-as-long-lasting-vaccine-memory-without-plasticity-towards-ifn%C3%AE-cells
#4
Som Gowda Nanjappa, Andrew J McDermott, J Scott Fites, Kevin Galles, Marcel Wüthrich, George S Deepe, Bruce S Klein
Our understanding of persistence and plasticity of IL-17A+ memory T cells is clouded by conflicting results in models analyzing T helper 17 cells. We studied memory IL-17A+ CD8+ T-cell (Tc17) homeostasis, persistence and plasticity during fungal vaccine immunity. We report that vaccine-induced memory Tc17 cells persist with high fidelity to the type 17 phenotype. Tc17 cells persisted durably for a year as functional IL-17A+ memory cells without converting to IFNγ+ (Tc1) cells, although they produced multiple type I cytokines in the absence of residual vaccine antigen...
May 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542576/ebola-virus-glycoprotein-directly-triggers-t-lymphocyte-death-despite-of-the-lack-of-infection
#5
Mathieu Iampietro, Patrick Younan, Andrew Nishida, Mukta Dutta, Ndongala Michel Lubaki, Rodrigo I Santos, Richard A Koup, Michael G Katze, Alexander Bukreyev
Fatal outcomes of Ebola virus (EBOV) infections are typically preceded by a 'sepsis-like' syndrome and lymphopenia despite T cells being resistant to Ebola infection. The mechanisms that lead to T lymphocytes death remain largely unknown; however, the degree of lymphopenia is highly correlative with fatalities. Here we investigated whether the addition of EBOV or its envelope glycoprotein (GP) to isolated primary human CD4+ T cells induced cell death. We observed a significant decrease in cell viability in a GP-dependent manner, which is suggestive of a direct role of GP in T cell death...
May 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542569/fas-associated-factor-1-positively-regulates-type-i-interferon-response-to-rna-virus-infection-by-targeting-nlrx1
#6
Jae-Hoon Kim, Min-Eun Park, Chamilani Nikapitiya, Tae-Hwan Kim, Md Bashir Uddin, Hyun-Cheol Lee, Eunhee Kim, Jin Yeul Ma, Jae U Jung, Chul-Joong Kim, Jong-Soo Lee
FAS-associated factor-1 (FAF1) is a component of the death-inducing signaling complex involved in Fas-mediated apoptosis. It regulates NF-κB activity, ubiquitination, and proteasomal degradation. Here, we found that FAF1 positively regulates the type I interferon pathway. FAF1gt/gt mice, which deficient in FAF1, and FAF1 knockdown immune cells were highly susceptible to RNA virus infection and showed low levels of inflammatory cytokines and type I interferon (IFN) production. FAF1 was bound competitively to NLRX1 and positively regulated type I IFN signaling by interfering with the interaction between NLRX1 and MAVS, thereby freeing MAVS to bind RIG-I, which switched on the MAVS-RIG-I-mediated antiviral signaling cascade...
May 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542528/adaptation-of-candida-albicans-to-environmental-ph-induces-cell-wall-remodelling-and-enhances-innate-immune-recognition
#7
Sarah L Sherrington, Eleanor Sorsby, Nabeel Mahtey, Pizga Kumwenda, Megan D Lenardon, Ian Brown, Elizabeth R Ballou, Donna M MacCallum, Rebecca A Hall
Candida albicans is able to proliferate in environments that vary dramatically in ambient pH, a trait required for colonising niches such as the stomach, vaginal mucosal and the GI tract. Here we show that growth in acidic environments involves cell wall remodelling which results in enhanced chitin and β-glucan exposure at the cell wall periphery. Unmasking of the underlying immuno-stimulatory β-glucan in acidic environments enhanced innate immune recognition of C. albicans by macrophages and neutrophils, and induced a stronger proinflammatory cytokine response, driven through the C-type lectin-like receptor, Dectin-1...
May 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542482/down-regulation-of-macrophage-ifngr1-exacerbates-systemic-l-monocytogenes-infection
#8
Emily M Eshleman, Christine Delgado, Staci J Kearney, Rachel S Friedman, Laurel L Lenz
Interferons (IFNs) target macrophages to regulate inflammation and resistance to microbial infections. The type II IFN (IFNγ) acts on a cell surface receptor (IFNGR) to promote gene expression that enhance macrophage inflammatory and anti-microbial activity. Type I IFNs can dampen macrophage responsiveness to IFNγ and are associated with increased susceptibility to numerous bacterial infections. The precise mechanisms responsible for these effects remain unclear. Type I IFNs silence macrophage ifngr1 transcription and thus reduce cell surface expression of IFNGR1...
May 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542477/mycobacterium-tuberculosis-arrests-host-cycle-at-the-g1-s-transition-to-establish-long-term-infection
#9
Bridgette M Cumming, Md Aejazur Rahman, Dirk A Lamprecht, Kyle H Rohde, Vikram Saini, John H Adamson, David G Russell, Adrie J C Steyn
Signals modulating the production of Mycobacterium tuberculosis (Mtb) virulence factors essential for establishing long-term persistent infection are unknown. The WhiB3 redox regulator is known to regulate the production of Mtb virulence factors, however the mechanisms of this modulation are unknown. To advance our understanding of the mechanisms involved in WhiB3 regulation, we performed Mtb in vitro, intraphagosomal and infected host expression analyses. Our Mtb expression analyses in conjunction with extracellular flux analyses demonstrated that WhiB3 maintains bioenergetic homeostasis in response to available carbon sources found in vivo to establish Mtb infection...
May 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542641/platelet-proteome-reveals-novel-pathways-of-platelet-activation-and-platelet-mediated-immunoregulation-in-dengue
#10
Monique Ramos de Oliveira Trugilho, Eugenio Damaceno Hottz, Giselle Villa Flor Brunoro, André Teixeira-Ferreira, Paulo Costa Carvalho, Gustavo Adolfo Salazar, Guy A Zimmerman, Fernando A Bozza, Patrícia T Bozza, Jonas Perales
Dengue is the most prevalent human arbovirus disease worldwide. Dengue virus (DENV) infection causes syndromes varying from self-limiting febrile illness to severe dengue. Although dengue pathophysiology is not completely understood, it is widely accepted that increased inflammation plays important roles in dengue pathogenesis. Platelets are blood cells classically known as effectors of hemostasis which have been increasingly recognized to have major immune and inflammatory activities. Nevertheless, the phenotype and effector functions of platelets in dengue pathogenesis are not completely understood...
May 19, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542587/seminal-plasma-induces-inflammation-and-enhances-hiv-1-replication-in-human-cervical-tissue-explants
#11
Andrea Introini, Stéphanie Boström, Frideborg Bradley, Anna Gibbs, Axel Glaessgen, Annelie Tjernlund, Kristina Broliden
The most immediate and evident effect of mucosal exposure to semen in vivo is a local release of proinflammatory mediators accompanied by an influx of leukocytes into the female genital mucosa (FGM). The implication of such response in HIV-1 transmission has never been addressed due to limitations of currently available experimental models. Using human tissue explants from the uterine cervix, we developed a system of mucosal exposure to seminal plasma (SP) that supports HIV-1 replication. Treatment of ectocervical explants with SP resulted in the upregulation of inflammatory and growth factors, including IL-6, TNF, CCL5, CCL20, CXCL1, and CXCL8, and IL1A, CSF2, IL7, PTGS2, as evaluated by measuring protein levels in explant conditioned medium (ECM) and gene expression in tissue...
May 19, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542478/structural-basis-of-nectin-1-recognition-by-pseudorabies-virus-glycoprotein-d
#12
An Li, Guangwen Lu, Jianxun Qi, Lili Wu, Kegong Tian, Tingrong Luo, Yi Shi, Jinghua Yan, George F Gao
An early and yet indispensable step in the alphaherpesvirus infection is the engagement of host receptors by the viral envelope glycoprotein D (gD). Of the thus-far identified gD receptors, nectin-1 is likely the most effective in terms of its wide usage by multiple alphaherpesviruses for cell entry. The molecular basis of nectin-1 recognition by the gD protein is therefore an interesting scientific question in the alphaherpesvirus field. Previous studies focused on the herpes simplex virus (HSV) of the Simplexvirus genus, for which both the free gD structure and the gD/nectin-1 complex structure were reported at high resolutions...
May 19, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28542609/potent-and-selective-inhibition-of-pathogenic-viruses-by-engineered-ubiquitin-variants
#13
Wei Zhang, Ben A Bailey-Elkin, Robert C M Knaap, Baldeep Khare, Tim J Dalebout, Garrett G Johnson, Puck B van Kasteren, Nigel J McLeish, Jun Gu, Wenguang He, Marjolein Kikkert, Brian L Mark, Sachdev S Sidhu
The recent Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola and Zika virus outbreaks exemplify the continued threat of (re-)emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV) encode deubiquitinating (DUB) enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) from cellular proteins to suppress host antiviral innate immune responses...
May 18, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28545104/pkng-senses-amino-acid-availability-to-control-metabolism-and-virulence-of-mycobacterium-tuberculosis
#14
Barbara Rieck, Giulia Degiacomi, Michael Zimmermann, Alessandro Cascioferro, Francesca Boldrin, Natalie R Lazar-Adler, Andrew R Bottrill, Fabien le Chevalier, Wafa Frigui, Marco Bellinzoni, María-Natalia Lisa, Pedro M Alzari, Liem Nguyen, Roland Brosch, Uwe Sauer, Riccardo Manganelli, Helen M O'Hare
Sensing and response to changes in nutrient availability are essential for the lifestyle of environmental and pathogenic bacteria. Serine/threonine protein kinase G (PknG) is required for virulence of the human pathogen Mycobacterium tuberculosis, and its putative substrate GarA regulates the tricarboxylic acid cycle in M. tuberculosis and other Actinobacteria by protein-protein binding. We sought to understand the stimuli that lead to phosphorylation of GarA, and the roles of this regulatory system in pathogenic and non-pathogenic bacteria...
May 17, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28545061/microbiota-induced-peritrophic-matrix-regulates-midgut-homeostasis-and-prevents-systemic-infection-of-malaria-vector-mosquitoes
#15
Faye H Rodgers, Mathilde Gendrin, Claudia A S Wyer, George K Christophides
Manipulation of the mosquito gut microbiota can lay the foundations for novel methods for disease transmission control. Mosquito blood feeding triggers a significant, transient increase of the gut microbiota, but little is known about the mechanisms by which the mosquito controls this bacterial growth whilst limiting inflammation of the gut epithelium. Here, we investigate the gut epithelial response to the changing microbiota load upon blood feeding in the malaria vector Anopheles coluzzii. We show that the synthesis and integrity of the peritrophic matrix, which physically separates the gut epithelium from its luminal contents, is microbiota dependent...
May 17, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28498847/paradoxical-myeloid-derived-suppressor-cell-reduction-in-the-bone-marrow-of-siv-chronically-infected-macaques
#16
Yongjun Sui, Blake Frey, Yichuan Wang, Rolf Billeskov, Shweta Kulkarni, Katherine McKinnon, Tracy Rourke, Linda Fritts, Christopher J Miller, Jay A Berzofsky
Myeloid derived suppressor cells (MDSCs), which suppress anti-tumor or anti-viral immune responses, are expanded in the peripheral blood and tissues of patients/animals with cancer or viral infectious diseases. We here show that in chronic SIV infection of Indian rhesus macaques, the frequency of MDSCs in the bone marrow (BM) was paradoxically and unexpectedly decreased, but increased in peripheral blood. Reduction of BM MDSCs was found in both CD14+MDSC and Lin-CD15+MDSC subsets. The reduction of MDSCs correlated with high plasma viral loads and low CD4+ T cell counts, suggesting that depletion of BM MDSCs was associated with SIV/AIDS disease progression...
May 12, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28494029/characterization-of-mir-122-independent-propagation-of-hcv
#17
Chikako Ono, Takasuke Fukuhara, Daisuke Motooka, Shota Nakamura, Daisuke Okuzaki, Satomi Yamamoto, Tomokazu Tamura, Hiroyuki Mori, Asuka Sato, Kentaro Uemura, Yuzy Fauzyah, Takeshi Kurihara, Takahiro Suda, Akira Nishio, Su Su Hmwe, Toru Okamoto, Tomohide Tatsumi, Tetsuo Takehara, Kazuaki Chayama, Takaji Wakita, Kazuhiko Koike, Yoshiharu Matsuura
miR-122, a liver-specific microRNA, is one of the determinants for liver tropism of hepatitis C virus (HCV) infection. Although miR-122 is required for efficient propagation of HCV, we have previously shown that HCV replicates at a low rate in miR-122-deficient cells, suggesting that HCV-RNA is capable of propagating in an miR-122-independent manner. We herein investigated the roles of miR-122 in both the replication of HCV-RNA and the production of infectious particles by using miR-122-knockout Huh7 (Huh7-122KO) cells...
May 11, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28489917/mucosal-fluid-glycoprotein-dmbt1-suppresses-twitching-motility-and-virulence-of-the-opportunistic-pathogen-pseudomonas-aeruginosa
#18
Jianfang Li, Matteo M E Metruccio, David J Evans, Suzanne M J Fleiszig
It is generally thought that mucosal fluids protect underlying epithelial surfaces against opportunistic infection via their antimicrobial activity. However, our published data show that human tear fluid can protect against the major opportunistic pathogen Pseudomonas aeruginosa independently of bacteriostatic activity. Here, we explored the mechanisms for tear protection, focusing on impacts of tear fluid on bacterial virulence factor expression. Results showed that tear fluid suppressed twitching motility, a type of surface-associated movement conferred by pili...
May 10, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28489916/generational-distribution-of-a-candida-glabrata-population-resilient-old-cells-prevail-while-younger-cells-dominate-in-the-vulnerable-host
#19
Tejas Bouklas, Luz Alonso-Crisóstomo, Tamás Székely, Elizabeth Diago-Navarro, Erika P Orner, Kalie Smith, Mansa A Munshi, Maurizio Del Poeta, Gábor Balázsi, Bettina C Fries
Similar to other yeasts, the human pathogen Candida glabrata ages when it undergoes asymmetric, finite cell divisions, which determines its replicative lifespan. We sought to investigate if and how aging changes resilience of C. glabrata populations in the host environment. Our data demonstrate that old C. glabrata are more resistant to hydrogen peroxide and neutrophil killing, whereas young cells adhere better to epithelial cell layers. Consequently, virulence of old compared to younger C. glabrata cells is enhanced in the Galleria mellonella infection model...
May 10, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28481926/delineating-morbillivirus-entry-dissemination-and-airborne-transmission-by-studying-in-vivo-competition-of-multicolor-canine-distemper-viruses-in-ferrets
#20
Rory D de Vries, Martin Ludlow, Alwin de Jong, Linda J Rennick, R Joyce Verburgh, Geert van Amerongen, Debby van Riel, Peter R W A van Run, Sander Herfst, Thijs Kuiken, Ron A M Fouchier, Albert D M E Osterhaus, Rik L de Swart, W Paul Duprex
Identification of cellular receptors and characterization of viral tropism in animal models have vastly improved our understanding of morbillivirus pathogenesis. However, specific aspects of viral entry, dissemination and transmission remain difficult to recapitulate in animal models. Here, we used three virologically identical but phenotypically distinct recombinant (r) canine distemper viruses (CDV) expressing different fluorescent reporter proteins for in vivo competition and airborne transmission studies in ferrets (Mustela putorius furo)...
May 8, 2017: PLoS Pathogens
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