Enterovirus 71 (EV-A71) receptors that have been identified to date cannot fully explain the pathogenesis of EV-A71, which is an important global cause of hand-foot-and-mouth disease and life-threatening encephalitis. We identified an interferon-gamma (IFNγ)-inducible EV-A71 cellular entry factor, human tryptophanyl-tRNA synthetase (hWARS), using genome-wide RNAi library screening. The importance of hWARS in mediating virus entry and infectivity was confirmed by virus attachment, in vitro pull-down, antibody/antigen blocking, and CRISPR/Cas9. Upon IFNγ treatment, induced hyperexpression and plasma membrane translocation of hWARS were observed, which sensitized semi-permissive (human neuronal NT2)/non-permissive (mouse fibroblast L929) cells to EV-A71 infection. Our hWARS-transduced mouse infection model showed pathological changes similar to patients with severe EV-A71 infection. The expression of hWARS is also required for productive infection by other human enteroviruses, including the clinically important CV-A16 and EV-D68. This is the first report on the discovery of an entry factor, hWARS, which can be induced by IFNγ for EV-A71. Given that a high level of IFNγ was observed in patients with severe EV-A71 infection, our findings extend the knowledge of the pathogenicity of EV-A71 in relation to the expression of entry factor upon IFNγ stimulation and the therapeutic options for treating severe EV-A71-associated complications.
Man Lung Yeung, Lilong Jia, Cyril C.Y. Yip, Jasper F.W. Chan, Jade L.L. Teng, Kwok-Hung Chan, Jian-Piao Cai, Chaoyu Zhang, Anna J. Zhang, Wan-Man Wong, Kin-Hang Kok, Susanna K.P. Lau, Patrick C.Y. Woo, Janice Y.C. Lo, Dong-Yan Jin, Shin-Ru Shih, Kwok-Yung Yuen
Federico Iovino, Disa L. Hammarlöf, Genevieve Garriss, Sarah Brovall, Priyanka Nannapaneni, Birgitta Henriques-Normark
Simone Lanini, Gina Portella, Francesco Vairo, Gary P Kobinger, Antonio Pesenti, Martin Langer, Soccoh Kabia, Giorgio Brogiato, Jackson Amone, Concetta Castilletti, Rossella Miccio, Alimuddin Zumla, Maria Rosaria Capobianchi, Antonino Di Caro, Gino Strada, Giuseppe Ippolito, INMI-EMERGENCY EBOV Sierra Leone Study group
Chronic infections induce a complex immune response that controls pathogen replication, but also causes pathology due to sustained inflammation. Ca2+ influx mediates T cell function and immunity to infection, and patients with inherited mutations in the gene encoding the Ca2+ channel ORAI1 or its activator stromal interaction molecule 1 (STIM1) are immunodeficient and prone to chronic infection by various pathogens, including
Ludovic Desvignes, Carl Weidinger, Patrick Shaw, Martin Vaeth, Theo Ribierre, Menghan Liu, Tawania Fergus, Lina Kozhaya, Lauren McVoy, Derya Unutmaz, Joel D. Ernst, Stefan Feske
Toidi Adekambi, Chris C. Ibegbu, Stephanie Cagle, Ameeta S. Kalokhe, Yun F. Wang, Yijuan Hu, Cheryl L. Day, Susan M. Ray, Jyothi Rengarajan
Nitric oxide (NO) production is critical for the host defense against intracellular pathogens; however, it is unclear whether NO-dependent control of intracellular organisms depends on cell-intrinsic or cell-extrinsic activity of NO. For example, NO production by infected phagocytes may enable these cells to individually control their pathogen burden. Alternatively, the ability of NO to diffuse across cell membranes might be critical for infection control. Here, using a murine ear infection model, we found that, during infection with the intracellular parasite
Romain Olekhnovitch, Bernhard Ryffel, Andreas J. Müller, Philippe Bousso
Development of host protective immunity against
Roanne Keeton, Nasiema Allie, Ivy Dambuza, Brian Abel, Nai-Jen Hsu, Boipelo Sebesho, Philippa Randall, Patricia Burger, Elizabeth Fick, Valerie F.J. Quesniaux, Bernhard Ryffel, Muazzam Jacobs
Biofilms are surface-attached agglomerations of microorganisms embedded in an extracellular matrix. Biofilm-associated infections are difficult to eradicate and represent a significant reservoir for disseminating and recurring serious infections. Infections involving biofilms frequently develop on indwelling medical devices in hospitalized patients, and Staphylococcus epidermidis is the leading cause of infection in this setting. However, the molecular determinants of biofilm dissemination are unknown. Here we have demonstrated that specific secreted, surfactant-like S. epidermidis peptides — the β subclass of phenol-soluble modulins (PSMs) — promote S. epidermidis biofilm structuring and detachment in vitro and dissemination from colonized catheters in a mouse model of device-related infection. Our study establishes in vivo significance of biofilm detachment mechanisms for the systemic spread of biofilm-associated infection and identifies the effectors of biofilm maturation and detachment in a premier biofilm-forming pathogen. Furthermore, by demonstrating that antibodies against PSMβ peptides inhibited bacterial spread from indwelling medical devices, we have provided proof of principle that interfering with biofilm detachment mechanisms may prevent dissemination of biofilm-associated infection.
Rong Wang, Burhan A. Khan, Gordon Y. C. Cheung, Thanh-Huy L. Bach, Max Jameson-Lee, Kok-Fai Kong, Shu Y. Queck, Michael Otto
Sickle cell disease (SCD) is characterized by intravascular hemolysis and inflammation coupled to a 400-fold greater incidence of invasive pneumococcal infection resulting in fulminant, lethal pneumococcal sepsis. Mechanistically, invasive infection is facilitated by a proinflammatory state that enhances receptor-mediated endocytosis of pneumococci into epithelial and endothelial cells. As statins reduce chronic inflammation, in addition to their serum cholesterol-lowering effects, we hypothesized that statin therapy might improve the outcome of pneumococcal infection in SCD. In this study, we tested this hypothesis in an experimental SCD mouse model and found that statin therapy prolonged survival following pneumococcal challenge. The protective effect resulted in part from decreased platelet-activating factor receptor expression on endothelia and epithelia, which led to reduced bacterial invasion. An additional protective effect resulted from inhibition of host cell lysis by pneumococcal cholesterol-dependent cytotoxins (CDCs), including pneumolysin. We conclude therefore that statins may be of prophylactic benefit against invasive pneumococcal disease in patients with SCD and, more broadly, in settings of bacterial pathogenesis driven by receptor-mediated endocytosis and the CDC class of toxins produced by Gram-positive invasive bacteria.
Jason W. Rosch, Angela R. Boyd, Ernesto Hinojosa, Tamara Pestina, Yunming Hu, Derek A. Persons, Carlos J. Orihuela, Elaine I. Tuomanen
Candida parapsilosis is a major cause of human disease, yet little is known about the pathogen’s virulence. We have developed an efficient gene deletion system for C. parapsilosis based on the repeated use of the dominant nourseothricin resistance marker (caSAT1) and its subsequent deletion by FLP-mediated, site-specific recombination. Using this technique, we deleted the lipase locus in the C. parapsilosis genome consisting of adjacent genes CpLIP1 and CpLIP2. Additionally we reconstructed the CpLIP2 gene, which restored lipase activity. Lipolytic activity was absent in the null mutants, whereas the WT, heterozygous, and reconstructed mutants showed similar lipase production. Biofilm formation was inhibited with lipase-negative mutants and their growth was significantly reduced in lipid-rich media. The knockout mutants were more efficiently ingested and killed by J774.16 and RAW 264.7 macrophage-like cells. Additionally, the lipase-negative mutants were significantly less virulent in infection models that involve inoculation of reconstituted human oral epithelium or murine intraperitoneal challenge. These studies represent what we believe to be the first targeted disruption of a gene in C. parapsilosis and show that C. parapsilosis–secreted lipase is involved in disease pathogenesis. This efficient system for targeted gene deletion holds great promise for rapidly enhancing our knowledge of the biology and virulence of this increasingly common invasive fungal pathogen.
Attila Gácser, David Trofa, Wilhelm Schäfer, Joshua D. Nosanchuk
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