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PLoS Pathogens

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https://www.readbyqxmd.com/read/28225830/ex-vivo-activation-of-cd4-t-cells-from-donors-on-suppressive-art-can-lead-to-sustained-production-of-infectious-hiv-1-from-a-subset-of-infected-cells
#1
John K Bui, Elias K Halvas, Elizabeth Fyne, Michele D Sobolewski, Dianna Koontz, Wei Shao, Brian Luke, Feiyu F Hong, Mary F Kearney, John W Mellors
The fate of HIV-infected cells after reversal of proviral latency is not well characterized. Simonetti, et al. recently showed that CD4+ T-cells containing intact proviruses can clonally expand in vivo and produce low-level infectious viremia. We hypothesized that reversal of HIV latency by activation of CD4+ T-cells can lead to the expansion of a subset of virus-producing cells rather than their elimination. We established an ex vivo cell culture system involving stimulation of CD4+ T-cells from donors on suppressive antiretroviral therapy (ART) with PMA/ionomycin (day 1-7), followed by rest (day 7-21), and then repeat stimulation (day 21-28), always in the presence of high concentrations of raltegravir and efavirenz to effectively block new cycles of viral replication...
February 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28225819/lipid-interactions-and-angle-of-approach-to-the-hiv-1-viral-membrane-of-broadly-neutralizing-antibody-10e8-insights-for-vaccine-and-therapeutic-design
#2
Adriana Irimia, Andreia M Serra, Anita Sarkar, Ronald Jacak, Oleksandr Kalyuzhniy, Devin Sok, Karen L Saye-Francisco, Torben Schiffner, Ryan Tingle, Michael Kubitz, Yumiko Adachi, Robyn L Stanfield, Marc C Deller, Dennis R Burton, William R Schief, Ian A Wilson
Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater neutralizing breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The 10E8 epitope has been identified as the conserved membrane proximal external region (MPER) of gp41 subunit of the envelope (Env) viral glycoprotein and is a major vaccine target. However, the MPER is proximal to the viral membrane and may be laterally inserted into the membrane in the Env prefusion form. Nevertheless, 10E8 has not been reported to have significant lipid-binding reactivity...
February 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28222188/the-thermodynamics-of-pr55gag-rna-interaction-regulate-the-assembly-of-hiv
#3
Hanumant S Tanwar, Keith K Khoo, Megan Garvey, Lynne Waddington, Andrew Leis, Marcel Hijnen, Tony Velkov, Geoff J Dumsday, William J McKinstry, Johnson Mak
The interactions that occur during HIV Pr55Gag oligomerization and genomic RNA packaging are essential elements that facilitate HIV assembly. However, mechanistic details of these interactions are not clearly defined. Here, we overcome previous limitations in producing large quantities of full-length recombinant Pr55Gag that is required for isothermal titration calorimetry (ITC) studies, and we have revealed the thermodynamic properties of HIV assembly for the first time. Thermodynamic analysis showed that the binding between RNA and HIV Pr55Gag is an energetically favourable reaction (ΔG<0) that is further enhanced by the oligomerization of Pr55Gag...
February 21, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28222186/alpk1-controls-tifa-traf6-dependent-innate-immunity-against-heptose-1-7-bisphosphate-of-gram-negative-bacteria
#4
Milica Milivojevic, Anne-Sophie Dangeard, Christoph Alexander Kasper, Therese Tschon, Mario Emmenlauer, Claudine Pique, Pamela Schnupf, Julie Guignot, Cécile Arrieumerlou
During infection by invasive bacteria, epithelial cells contribute to innate immunity via the local secretion of inflammatory cytokines. These are directly produced by infected cells or by uninfected bystanders via connexin-dependent cell-cell communication. However, the cellular pathways underlying this process remain largely unknown. Here we perform a genome-wide RNA interference screen and identify TIFA and TRAF6 as central players of Shigella flexneri and Salmonella typhimurium-induced interleukin-8 expression...
February 21, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28212444/sumo-modification-of-a-heterochromatin-histone-demethylase-jmjd2a-enables-viral-gene-transactivation-and-viral-replication
#5
Wan-Shan Yang, Mel Campbell, Pei-Ching Chang
Small ubiquitin-like modifier (SUMO) modification of chromatin has profound effects on transcription regulation. By using Kaposi's sarcoma associated herpesvirus (KSHV) as a model, we recently demonstrated that epigenetic modification of viral chromatin by SUMO-2/3 is involved in regulating gene expression and viral reactivation. However, how this modification orchestrates transcription reprogramming through targeting histone modifying enzymes remains largely unknown. Here we show that JMJD2A, the first identified Jumonji C domain-containing histone demethylase, is the histone demethylase responsible for SUMO-2/3 enrichment on the KSHV genome during viral reactivation...
February 17, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28212430/a-calmodulin-like-protein-suppresses-rna-silencing-and-promotes-geminivirus-infection-by-degrading-sgs3-via-the-autophagy-pathway-in-nicotiana-benthamiana
#6
Fangfang Li, Nan Zhao, Zhenghe Li, Xiongbiao Xu, Yaqin Wang, Xiuling Yang, Shu-Sheng Liu, Aiming Wang, Xueping Zhou
A recently characterized calmodulin-like protein is an endogenous RNA silencing suppressor that suppresses sense-RNA induced post-transcriptional gene silencing (S-PTGS) and enhances virus infection, but the mechanism underlying calmodulin-like protein-mediated S-PTGS suppression is obscure. Here, we show that a calmodulin-like protein from Nicotiana benthamiana (NbCaM) interacts with Suppressor of Gene Silencing 3 (NbSGS3). Deletion analyses showed that domains essential for the interaction between NbSGS3 and NbCaM are also required for the subcellular localization of NbSGS3 and NbCaM suppressor activity...
February 17, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28212410/a-high-throughput-genetic-screen-identifies-previously-uncharacterized-borrelia-burgdorferi-genes-important-for-resistance-against-reactive-oxygen-and-nitrogen-species
#7
Meghan E Ramsey, Jenny A Hyde, Diana N Medina-Perez, Tao Lin, Lihui Gao, Maureen E Lundt, Xin Li, Steven J Norris, Jon T Skare, Linden T Hu
Borrelia burgdorferi, the causative agent of Lyme disease in humans, is exposed to reactive oxygen and nitrogen species (ROS and RNS) in both the tick vector and vertebrate reservoir hosts. B. burgdorferi contains a limited repertoire of canonical oxidative stress response genes, suggesting that novel gene functions may be important for protection of B. burgdorferi against ROS or RNS exposure. Here, we use transposon insertion sequencing (Tn-seq) to conduct an unbiased search for genes involved in resistance to nitric oxide, hydrogen peroxide, and tertiary-butyl hydroperoxide in vitro...
February 17, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28192542/functional-diversity-of-secreted-cestode-kunitz-proteins-inhibition-of-serine-peptidases-and-blockade-of-cation-channels
#8
Martín Fló, Mariana Margenat, Leonardo Pellizza, Martín Graña, Rosario Durán, Adriana Báez, Emilio Salceda, Enrique Soto, Beatriz Alvarez, Cecilia Fernández
We previously reported a multigene family of monodomain Kunitz proteins from Echinococcus granulosus (EgKU-1-EgKU-8), and provided evidence that some EgKUs are secreted by larval worms to the host interface. In addition, functional studies and homology modeling suggested that, similar to monodomain Kunitz families present in animal venoms, the E. granulosus family could include peptidase inhibitors as well as channel blockers. Using enzyme kinetics and whole-cell patch-clamp, we now demonstrate that the EgKUs are indeed functionally diverse...
February 13, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28192541/immune-driven-alterations-in-mucin-sulphation-is-an-important-mediator-of-trichuris-muris-helminth-expulsion
#9
Sumaira Z Hasnain, Paul A Dawson, Rohan Lourie, Peter Hutson, Hui Tong, Richard K Grencis, Michael A McGuckin, David J Thornton
Mucins are heavily glycosylated proteins that give mucus its gel-like properties. Moreover, the glycans decorating the mucin protein core can alter the protective properties of the mucus barrier. To investigate whether these alterations could be parasite-induced we utilized the Trichuris muris (T. muris) infection model, using different infection doses and strains of mice that are resistant (high dose infection in BALB/c and C57BL6 mice) or susceptible (high dose infection in AKR and low dose infection in BALB/c mice) to chronic infection by T...
February 13, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28192532/role-of-arf-gtpases-in-fungal-morphogenesis-and-virulence
#10
Hayet Labbaoui, Stéphanie Bogliolo, Vikram Ghugtyal, Norma V Solis, Scott G Filler, Robert A Arkowitz, Martine Bassilana
Virulence of the human fungal pathogen Candida albicans depends on the switch from budding to filamentous growth, which requires sustained membrane traffic and polarized growth. In many organisms, small GTPases of the Arf (ADP-ribosylation factor) family regulate membrane/protein trafficking, yet little is known about their role in fungal filamentous growth. To investigate these GTPases in C. albicans, we generated loss of function mutants in all 3 Arf proteins, Arf1-Arf3, and 2 Arf-like proteins, Arl1 and Arl3...
February 13, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28192531/multi-layered-control-of-galectin-8-mediated-autophagy-during-adenovirus-cell-entry-through-a-conserved-ppxy-motif-in-the-viral-capsid
#11
Charlotte Montespan, Shauna A Marvin, Sisley Austin, Andrew M Burrage, Benoit Roger, Fabienne Rayne, Muriel Faure, Edward M Campell, Carola Schneider, Rudolph Reimer, Kay Grünewald, Christopher M Wiethoff, Harald Wodrich
Cells employ active measures to restrict infection by pathogens, even prior to responses from the innate and humoral immune defenses. In this context selective autophagy is activated upon pathogen induced membrane rupture to sequester and deliver membrane fragments and their pathogen contents for lysosomal degradation. Adenoviruses, which breach the endosome upon entry, escape this fate by penetrating into the cytosol prior to autophagosome sequestration of the ruptured endosome. We show that virus induced membrane damage is recognized through Galectin-8 and sequesters the autophagy receptors NDP52 and p62...
February 13, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28192528/cd8-t-cell-cytotoxicity-mediates-pathology-in-the-skin-by-inflammasome-activation-and-il-1%C3%AE-production
#12
Fernanda O Novais, Augusto M Carvalho, Megan L Clark, Lucas P Carvalho, Daniel P Beiting, Igor E Brodsky, Edgar M Carvalho, Phillip Scott
Deregulated CD8+ T cell cytotoxicity plays a central role in enhancing disease severity in several conditions. However, we have little understanding of the mechanisms by which immunopathology develops as a consequence of cytotoxicity. Using murine models of inflammation induced by the protozoan parasite leishmania, and data obtained from patients with cutaneous leishmaniasis, we uncovered a previously unrecognized role for NLRP3 inflammasome activation and IL-1β release as a detrimental consequence of CD8+ T cell-mediated cytotoxicity, ultimately resulting in chronic inflammation...
February 13, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28192515/salmonella-typhimurium-disrupts-sirt1-ampk-checkpoint-control-of-mtor-to-impair-autophagy
#13
Raja Ganesan, Nina Judith Hos, Saray Gutierrez, Julia Fischer, Joanna Magdalena Stepek, Evmorphia Daglidu, Martin Krönke, Nirmal Robinson
During intracellular infections, autophagy significantly contributes to the elimination of pathogens, regulation of pro-inflammatory signaling, secretion of immune mediators and in coordinating the adaptive immune system. Intracellular pathogens such as S. Typhimurium have evolved mechanisms to circumvent autophagy. However, the regulatory mechanisms targeted by S. Typhimurium to modulate autophagy have not been fully resolved. Here we report that cytosolic energy loss during S. Typhimurium infection triggers transient activation of AMPK, an important checkpoint of mTOR activity and autophagy...
February 13, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28166307/picornavirus-rna-is-protected-from-cleavage-by-ribonuclease-during-virion-uncoating-and-transfer-across-cellular-and-model-membranes
#14
Elisabetta Groppelli, Hazel C Levy, Eileen Sun, Mike Strauss, Clare Nicol, Sarah Gold, Xiaowei Zhuang, Tobias J Tuthill, James M Hogle, David J Rowlands
Picornaviruses are non-enveloped RNA viruses that enter cells via receptor-mediated endocytosis. Because they lack an envelope, picornaviruses face the challenge of delivering their RNA genomes across the membrane of the endocytic vesicle into the cytoplasm to initiate infection. Currently, the mechanism of genome release and translocation across membranes remains poorly understood. Within the enterovirus genus, poliovirus, rhinovirus 2, and rhinovirus 16 have been proposed to release their genomes across intact endosomal membranes through virally induced pores, whereas one study has proposed that rhinovirus 14 releases its RNA following disruption of endosomal membranes...
February 6, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28212439/correction-type-i-interferon-receptor-deficiency-in-dendritic-cells-facilitates-systemic-murine-norovirus-persistence-despite-enhanced-adaptive-immunity
#15
Timothy J Nice, Lisa C Osborne, Vesselin T Tomov, David Artis, E John Wherry, Herbert W Virgin
[This corrects the article DOI: 10.1371/journal.ppat.1005684.].
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28212438/correction-increased-abundance-of-m-cells-in-the-gut-epithelium-dramatically-enhances-oral-prion-disease-susceptibility
#16
(no author information available yet)
[This corrects the article DOI: 10.1371/journal.ppat.1006075.].
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28207910/a-single-mutation-in-the-envelope-protein-modulates-flavivirus-antigenicity-stability-and-pathogenesis
#17
Leslie Goo, Laura A VanBlargan, Kimberly A Dowd, Michael S Diamond, Theodore C Pierson
The structural flexibility or 'breathing' of the envelope (E) protein of flaviviruses allows virions to sample an ensemble of conformations at equilibrium. The molecular basis and functional consequences of virus conformational dynamics are poorly understood. Here, we identified a single mutation at residue 198 (T198F) of the West Nile virus (WNV) E protein domain I-II hinge that regulates virus breathing. The T198F mutation resulted in a ~70-fold increase in sensitivity to neutralization by a monoclonal antibody targeting a cryptic epitope in the fusion loop...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28207896/rna-seq-analysis-of-chikungunya-virus-infection-and-identification-of-granzyme-a-as-a-major-promoter-of-arthritic-inflammation
#18
Jane A C Wilson, Natalie A Prow, Wayne A Schroder, Jonathan J Ellis, Helen E Cumming, Linden J Gearing, Yee Suan Poo, Adam Taylor, Paul J Hertzog, Francesca Di Giallonardo, Linda Hueston, Roger Le Grand, Bing Tang, Thuy T Le, Joy Gardner, Suresh Mahalingam, Pierre Roques, Phillip I Bird, Andreas Suhrbier
: Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28207890/mucosal-stromal-fibroblasts-markedly-enhance-hiv-infection-of-cd4-t-cells
#19
Jason A Neidleman, Joseph C Chen, Nargis Kohgadai, Janis A Müller, Anders Laustsen, Karthiga Thavachelvam, Karen S Jang, Christina M Stürzel, Jennifer J Jones, Christina Ochsenbauer, Avantika Chitre, Ma Somsouk, Maurice M Garcia, James F Smith, Ruth M Greenblatt, Jan Münch, Martin R Jakobsen, Linda C Giudice, Warner C Greene, Nadia R Roan
Understanding early events of HIV transmission within mucosal tissues is vital for developing effective prevention strategies. Here, we report that primary stromal fibroblasts isolated from endometrium, cervix, foreskin, male urethra, and intestines significantly increase HIV infection of CD4+ T cells-by up to 37-fold for R5-tropic HIV and 100-fold for X4-tropic HIV-without themselves becoming infected. Fibroblasts were more efficient than dendritic cells at trans-infection and mediate this response in the absence of the DC-SIGN and Siglec-1 receptors...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28207848/resolving-host-pathogen-interactions-by-dual-rna-seq
#20
REVIEW
Alexander J Westermann, Lars Barquist, Jörg Vogel
The transcriptome is a powerful proxy for the physiological state of a cell, healthy or diseased. As a result, transcriptome analysis has become a key tool in understanding the molecular changes that accompany bacterial infections of eukaryotic cells. Until recently, such transcriptomic studies have been technically limited to analyzing mRNA expression changes in either the bacterial pathogen or the infected eukaryotic host cell. However, the increasing sensitivity of high-throughput RNA sequencing now enables "dual RNA-seq" studies, simultaneously capturing all classes of coding and noncoding transcripts in both the pathogen and the host...
February 2017: PLoS Pathogens
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