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Interferon type I immunity

Cherrie D Thompson, Bharati Matta, Betsy J Barnes
The interferon regulatory factors (IRFs) are a family of master transcription factors that regulate pathogen-induced innate and acquired immune responses. Aberration(s) in IRF signaling pathways due to infection, genetic predisposition and/or mutation, which can lead to increased expression of type I interferon (IFN) genes, IFN-stimulated genes (ISGs), and other pro-inflammatory cytokines/chemokines, has been linked to the development of numerous diseases, including (but not limited to) autoimmune and cancer...
2018: Frontiers in Immunology
Lucy A Eddowes, Kinda Al-Hourani, Narayan Ramamurthy, Jamie Frankish, Hannah T Baddock, Cynthia Sandor, John D Ryan, Dahlene N Fusco, João Arezes, Eleni Giannoulatou, Sara Boninsegna, Stephane Chevaliez, Benjamin M J Owens, Chia Chi Sun, Paolo Fabris, Maria Teresa Giordani, Diego Martines, Slobodan Vukicevic, John Crowe, Herbert Y Lin, Jan Rehwinkel, Peter J McHugh, Marco Binder, Jodie L Babitt, Raymond T Chung, Matthew W Lawless, Andrew E Armitage, Caleb Webber, Paul Klenerman, Hal Drakesmith
Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity...
December 3, 2018: Nature Microbiology
Nancy Au-Yeung, Curt M Horvath
In response to virus infections, a cell-autonomous, transcription-based antiviral program is engaged to create resistance, impair pathogen replication, and alert professional cells in innate and adaptive immunity. This dual phase antiviral program consists of type I interferon (IFN) production followed by the response to IFN signaling. Pathogen recognition leads to activation of IRF and NFκB factors that function independently and together to recruit cellular coactivators that remodel chromatin, modify histones and activate RNA polymerase II (Pol II) at target gene loci, including the well-characterized IFNβ enhanceosome...
December 2018: Cytokine & Growth Factor Reviews
Nadeem Shabir, Amina Khatun, Salik Nazki, Suna Gu, Sang-Myoung Lee, Tai-Young Hur, Myoun-Sik Yang, Bumseok Kim, Won-Il Kim
BACKGROUND: Currently, an in vitro immunogenicity screening system for the immunological assessment of potential porcine reproductive and respiratory syndrome virus (PRRSV) vaccine candidates is highly desired. Thus, in the present study, two genetically divergent PRRSVs were characterized in vitro and in vivo to identify an in vitro system and immunological markers that predict the host immune response. Porcine alveolar macrophages (PAMs) and peripheral blood mononuclear cells (PBMCs) collected from PRRSV-negative pigs were used for in vitro immunological evaluation, and the response of these cells to VR2332c or JA142c were compared with those elicited in pigs challenged with the same viruses...
December 4, 2018: BMC Veterinary Research
Ge Li, Chunmei Hou, Shuaijie Dou, Jiacheng Zhang, Yanling Zhang, Yiqiong Liu, Zhiding Wang, He Xiao, Renxi Wang, Guojiang Chen, Yan Li, Jiannan Feng, Beifen Shen, Gencheng Han
T cell immunoglobulin and mucin domain protein 3 (Tim-3) is an immune checkpoint inhibitor in T cells and innate immune cells. The deregulated upregulation of Tim-3 is related to immune exhaustion in tumor and viral infection. To overcome Tim-3-mediated immune tolerance, we developed a novel monoclonal antibody against human Tim-3 (L3G) and investigated its roles in inhibiting Tim-3 signaling and overcoming immune tolerance in T cells and monocytes/macrophages. The administration of L3G to cultured peripheral blood mononuclear cells (PBMCs) significantly increased the production of IFN-γ and IL-2 and the expression of type I interferon...
December 1, 2018: Scandinavian Journal of Immunology
Julius C Fischer, Chia-Ching Lin, Simon Heidegger, Alexander Wintges, Martin Schlapschy, Matthias Beudert, Stephanie E Combs, Florian Bassermann, Arne Skerra, Tobias Haas, Hendrik Poeck
PURPOSE: Type I interferon (IFN-I) and IL-22 modulate regeneration of the thymus and intestinal epithelial cells (IECs) after cytotoxic stress like irradiation. Radiation-induced damage to thymic tissues and IECs is a crucial aspect during the pathogenesis of inadequate immune reconstitution and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative total body irradiation (TBI), respectively. IL-22 and IFN-I reduce severity of acute GVHD after allo-HSCT with myeloablative TBI...
November 29, 2018: International Journal of Radiation Oncology, Biology, Physics
Leonie Unterholzner, Jessica F Almine
Intracellular DNA and RNA sensors play a vital part in the innate immune response to viruses and other intracellular pathogens, causing the secretion of type I interferons, cytokines and chemokines from infected cells. Pathogen RNA can be detected by RIG-I-like receptors in the cytosol, while cytosolic DNA is recognised by DNA sensors such as cyclic GMP-AMP synthase (cGAS). The resulting local immune response, which is initiated within hours of infection, is able to eliminate many pathogens before they are able to establish an infection in the host...
November 30, 2018: Immunology
Ewa M Kosciuczuk, Swarna Mehrotra, Diana Saleiro, Barbara Kroczynska, Beata Majchrzak-Kita, Pawel Lisowski, Caroline Driehaus, Anna Rogalska, Acara Turner, Thomas Lienhoop, David Gius, Eleanor N Fish, Athanassios Vassilopoulos, Leonidas C Platanias
Type I interferons (IFNs) induce expression of multiple genes that control innate immune responses to invoke both antiviral and antineoplastic activities. Transcription of these interferon-stimulated genes (ISGs) occurs upon activation of the canonical Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathways. Phosphorylation and acetylation are both events crucial to tightly regulate expression of ISGs. Here, using mouse embryonic fibroblasts and an array of biochemical methods including immunoblotting and kinase assays, we show that sirtuin 2 (SIRT2), a member of the NAD-dependent protein deacetylase family, is involved in type I IFN signaling...
November 28, 2018: Journal of Biological Chemistry
Hawa Vahed, Anshu Agrawal, Ruchi Srivastava, Swayam Prakash, Pierre-Gregoire A Coulon, Soumyabrata Roy, Lbachir BenMohamed
A large proportion of the world population harbors herpes simplex virus type 1 (HSV-1) a major cause of infectious corneal blindness. HSV-specific CD8+ T cells protect from herpes infection and disease. However, the genomic, phenotypic and functional characteristics of CD8+ T cells associated with the protection seen in asymptomatic (ASYMP) individuals, who despite being infected, never experienced any recurrent herpetic disease, remains to be fully elucidated. In this investigation, we compared the phenotype, function, and level of expression of a comprehensive panel of 579 immune genes of memory CD8+ T cells, sharing the same HSV-1 epitope-specificities, and freshly isolated peripheral blood from well-characterized cohorts of protected ASYMP and non-protected symptomatic (SYMP) individuals, with a history of numerous episodes of recurrent herpetic disease using high throughput digital NanoString nCounter™ system and Flow Cytometry...
November 28, 2018: Journal of Virology
Katherine A Pillman, Gregory J Goodall, Cameron P Bracken, Michael P Gantier
Most microRNAs (miRNAs) are expressed as a mix of length isoforms (referred to as isomiRs). IsomiR stoichiometry can be differentially impacted upon cell stimulation, as recently evidenced by our group in the context of immune responses induced by type-I interferon (IFN). Here, we revisit published RNA-Seq datasets of human and mouse macrophages stimulated with bacterial products, at the isomiR level. We demonstrate that for several miRNAs, macrophage stimulation induces changes in isomiR stoichiometry. Critically, we find that changes in miRNA expression can be misinterpreted when miRNAs are quantified by RT-qPCR, as primers directed against canonical miRNA sequences may not equally target the different isomiRs that are regulated endogenously...
November 28, 2018: RNA
Jianfeng Shen, Wei Zhao, Zhenlin Ju, Lulu Wang, Yang Peng, Marilyne Labrie, Timothy A Yap, Gordon B Mills, Guang Peng
Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of single-stranded DNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations...
November 27, 2018: Cancer Research
Kelly M Shepardson, Kyle Larson, Laura L Johns, Kayla Stanek, Hanbyul Cho, Julia Wellham, Haley Henderson, Agnieszka Rynda-Apple
Influenza virus infections particularly when followed by bacterial superinfections (BSI) result in significant morbidities and mortalities especially during influenza pandemics. Type I interferons (IFNs) regulate both anti-influenza immunity and host susceptibility to subsequent BSIs. These type I IFNs consisting of, among others, 14 IFN-α's and a single IFN-β, are recognized by and signal through the heterodimeric type I IFN receptor (IFNAR) comprised of IFNAR1 and IFNAR2. However, the individual receptor subunits can bind IFN-β or IFN-α's independently of each other and induce distinct signaling...
2018: Frontiers in Immunology
Kiyoshi F Fukutani, Cristiana M Nascimento-Carvalho, Maiara L Bouzas, Juliana R Oliveira, Aldina Barral, Tim Dierckx, Ricardo Khouri, Helder I Nakaya, Bruno B Andrade, Johan Van Weyenbergh, Camila I de Oliveira
Acute respiratory infection (ARI) is the most frequent cause for hospitalization in infants and young children. Using multiplexed nCounter technology to digitally quantify 600 human mRNAs in parallel with 14 virus- and 5 bacterium-specific RNAs, we characterized viral and bacterial presence in nasopharyngeal aspirates (NPA) of 58 children with ARI and determined the corresponding in situ immune profiles. NPA contained different groups of organisms and these were classified into bacterial ( n = 27), viral ( n = 5), codetection [containing both viral and bacterial transcripts ( n = 21), or indeterminate intermediate where microbial load is below threshold ( n = 5)]...
2018: Frontiers in Microbiology
Krystal K Lum, Bokai Song, Joel D Federspiel, Benjamin A Diner, Timothy Howard, Ileana M Cristea
Viral DNA sensing is an essential component of the mammalian innate immune response. Upon binding viral DNA, the cyclic-GMP-AMP synthase (cGAS) catalyzes the production of cyclic dinucleotides to induce type I interferons. However, little is known about how cGAS is homeostatically maintained or regulated upon infection. Here, we define cytoplasmic cGAS interactions with cellular and viral proteins upon herpes simplex virus type 1 (HSV-1) infection in primary human fibroblasts. We compare several HSV-1 strains (wild-type, d109, d106) that induce cytokine responses and apoptosis and place cGAS interactions in the context of temporal proteome alterations using isobaric-labeling mass spectrometry...
November 12, 2018: Cell Systems
Xiao Yu, Yang Du, Chunmei Cai, Baowei Cai, Motao Zhu, Changsheng Xing, Peng Tan, Meng Lin, Jian Wu, Jian Li, Mingjun Wang, Helen Y Wang, Xin-Zhuan Su, Rong-Fu Wang
The inflammasome plays a critical role in inflammation and immune responses against pathogens. However, whether or how inflammasome activation regulates type I interferon (IFN-I) signaling in the context of malaria infection remain unknown. Here we show mice deficient in inflammasome sensors AIM2, NLRP3 or adaptor Caspase-1 produce high levels of IFN-I cytokines and are resistant to lethal Plasmodium yoelii YM infection. Inactivation of inflammasome signaling reduces interleukin (IL)-1β production, but increases IFN-I production...
November 23, 2018: Nature Communications
Jin-Shan Ran, Jie Jin, Xian-Xian Zhang, Ye Wang, Peng Ren, Jing-Jing Li, Ling-Qian Yin, Zhi-Qiang Li, Dan Lan, Yao-Dong Hu, Yi-Ping Liu
Innate immunity is an essential line of defense against pathogen invasion which is gained at birth, and the mechanism involved is mainly to identify pathogen-associated molecular patterns through pattern recognition receptors. STING (stimulator of interferon genes) is a signal junction molecule that hosts the perception of viral nucleic acids and produces type I interferon response, which plays a crucial role in innate immunity. However, relatively few studies have investigated the molecular characterization, tissue distribution, and potential function of STING in chickens...
November 22, 2018: International Journal of Molecular Sciences
Elisa Fanunza, Aldo Frau, Angela Corona, Enzo Tramontano
Upon viral infection, the interferon (IFN) system triggers potent antiviral mechanisms limiting viral growth and spread. Hence, to sustain their infection, viruses evolved efficient counteracting strategies to evade IFN control. Ebola virus (EBOV), member of the family Filoviridae, is one of the most virulent and deadly pathogen ever faced by humans. Etiological agent of the Ebola virus disease (EVD), EBOV can be undoubtedly considered the perfect example of a powerful inhibitor of the host organism immune response activation...
November 23, 2018: Infectious Disorders Drug Targets
Lori Broderick
The autoinflammatory diseases encompass approximately 30 monogenic disorders in which inborn errors in the innate immune system lead to episodic systemic inflammation. Largely mediated by dysregulation of myeloid cells, interleukin (IL)-1β, type I interferon, and NF-κB, these disorders have rapidly expanded over the past several years, and increasing numbers of patients identified. Crossover disorders, bridging autoinflammation and immunodeficiency, have recently been described. This article focuses on the clinical presentation of IL-1 and interferon-driven autoinflammatory disorders, and discusses novel diseases with features of immunodeficiency...
February 2019: Immunology and Allergy Clinics of North America
Brock G Bennion, Harshad Ingle, Teresa L Ai, Cathrine A Miner, Derek J Platt, Amber M Smith, Megan T Baldridge, Jonathan J Miner
We previously generated STING N153S knockin mice that have a human disease-associated gain-of-function mutation in STING. Patients with this mutation (STING N154S in human) develop STING-associated vasculopathy with onset in infancy (SAVI), a severe pediatric autoinflammatory disease characterized by pulmonary fibrosis. Since this mutation promotes up-regulation of antiviral type I interferon-stimulated genes (ISGs), we hypothesized that STING N153S knockin mice may develop more severe autoinflammatory disease in response to a virus challenge...
November 21, 2018: Journal of Virology
Rosa M Rubio, Daniel P Depledge, Christopher Bianco, Letitia Thompson, Ian Mohr
Modification of mRNA by N 6 -adenosine methylation (m6 A) on internal bases influences gene expression in eukaryotes. How the dynamic genome-wide landscape of m6 A-modified mRNAs impacts virus infection and host immune responses remains poorly understood. Here, we show that type I interferon (IFN) production triggered by dsDNA or human cytomegalovirus (HCMV) is controlled by the cellular m6 A methyltrasferase subunit METTL14 and ALKBH5 demethylase. While METTL14 depletion reduced virus reproduction and stimulated dsDNA- or HCMV-induced IFNB1 mRNA accumulation, ALKBH5 depletion had the opposite effect...
November 21, 2018: Genes & Development
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