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Agata Michalska, Katarzyna Blaszczyk, Joanna Wesoly, Hans A R Bluyssen
Interferon (IFN)-I and IFN-II both induce IFN-stimulated gene (ISG) expression through Janus kinase (JAK)-dependent phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2. STAT1 homodimers, known as γ-activated factor (GAF), activate transcription in response to all types of IFNs by direct binding to IFN-II activation site (γ-activated sequence)-containing genes. Association of interferon regulatory factor (IRF) 9 with STAT1-STAT2 heterodimers [known as interferon-stimulated gene factor 3 (ISGF3)] or with STAT2 homodimers (STAT2/IRF9) in response to IFN-I, redirects these complexes to a distinct group of target genes harboring the interferon-stimulated response element (ISRE)...
2018: Frontiers in Immunology
Yoshinori Kitagawa, Madoka Sakai, Masayuki Shimojima, Masayuki Saijo, Masae Itoh, Bin Gotoh
The nonstructural protein NSs of severe fever with thrombocytopenia syndrome phlebovirus blocks type I interferon (IFN)-stimulated JAK-STAT signaling. However, there is continuing controversy as to whether NSs targets STAT1 or STAT2 or both for this blockade. The present study was designed to gain a further understanding of the blockade mechanism. Immunoprecipitation experiments revealed a stronger interaction of NSs with STAT2 than with any other component constituting the JAK-STAT pathway. Expression of NSs resulted in the formation of cytoplasmic inclusion bodies (IBs), and affected cytoplasmic distribution of STAT2...
June 7, 2018: Microbes and Infection
Erica L Johnson, Sahithi Boggavarapu, Elan S Johnson, Asim Lal, Parth Agrawal, Siddhartha Kumar Bhaumik, Kaja Murali-Krishna, Rana Chakraborty
Several co-pathogens that pose threats to the fetus during gestation, including human cytomegalovirus (HCMV), may also contribute MTCT of HIV-1. Within endemic settings, associations between maternal HCMV viral load and increased incidence of MTCT of HIV-1 are documented; however, the mechanisms that promote transmission are poorly characterized. Here we demonstrate that HCMV co-infection enhances susceptibility and viral replication of HIV-1 in placental macrophages (Hofbauer cells) in vitro. Consistent with enhanced viral susceptibility, HCMV exposure upregulates CCR5 and CD80 expression on Hofbauer cells...
May 31, 2018: Journal of Infectious Diseases
Huiying Li, Lei Xing, Nan Zhao, Jiaqi Wang, Nan Zheng
As a typical product in the Miallard reaction, research on the quantitative detection of furosine is abundant, while its bioactivities and toxic effects are still unclear. Our own work recently demonstrated the induction of furosine on apoptosis in HepG2 cells, while the related mechanism remained elusive. In this study, the effects of furosine on cell viability and apoptosis were detected to select the proper dosage, and transcriptomics detection and data analysis were performed to screen out the special genes...
May 31, 2018: International Journal of Molecular Sciences
Mohamad S Hakim, Sunrui Chen, Shihao Ding, Yuebang Yin, Aqsa Ikram, Xiao-Xia Ma, Wenshi Wang, Maikel P Peppelenbosch, Qiuwei Pan
Rotavirus (RV) primarily infects enterocytes and results in severe diarrhea, particularly in children. It is known that the host immune responses determine the outcome of viral infections. Following infections, interferons (IFNs) are produced as the first and the main anti-viral cytokines to combat the virus. Here we showed that RV predominantly induced type III IFNs (IFN-λ1), and to a less extent, type I IFNs (IFN-α and IFN-β) in human intestinal cells. However, it did not produce detectable IFN proteins and thus, was not sufficient to inhibit RV replication...
May 29, 2018: Scientific Reports
Matthew J Gorman, Elizabeth A Caine, Konstantin Zaitsev, Matthew C Begley, James Weger-Lucarelli, Melissa B Uccellini, Shashank Tripathi, Juliet Morrison, Boyd L Yount, Kenneth H Dinnon, Claudia Rückert, Michael C Young, Zhe Zhu, Shelly J Robertson, Kristin L McNally, Jing Ye, Bin Cao, Indira U Mysorekar, Gregory D Ebel, Ralph S Baric, Sonja M Best, Maxim N Artyomov, Adolfo Garcia-Sastre, Michael S Diamond
Progress toward understanding Zika virus (ZIKV) pathogenesis is hindered by lack of immunocompetent small animal models, in part because ZIKV fails to effectively antagonize Stat2-dependent interferon (IFN) responses in mice. To address this limitation, we first passaged an African ZIKV strain (ZIKV-Dak-41525) through Rag1-/- mice to obtain a mouse-adapted virus (ZIKV-Dak-MA) that was more virulent than ZIKV-Dak-41525 in mice treated with an anti-Ifnar1 antibody. A G18R substitution in NS4B was the genetic basis for the increased replication, and resulted in decreased IFN-β production, diminished IFN-stimulated gene expression, and the greater brain infection observed with ZIKV-Dak-MA...
May 9, 2018: Cell Host & Microbe
Vu Thuy Khanh Le-Trilling, Kerstin Wohlgemuth, Meike U Rückborn, Andreja Jagnjic, Fabienne Maaßen, Lejla Timmer, Benjamin Katschinski, Mirko Trilling
Pathogen encounter induces interferons which signal via Janus kinases and STAT transcription factors to establish an antiviral state. However, host and pathogens are situated in a continuous arms race which shapes host evolution towards optimized immune responses and the pathogens towards enhanced immune evasive properties.Mouse cytomegalovirus (MCMV) counteracts interferon responses by pM27-mediated degradation of STAT2 which directly affects the signaling of type I as well as type III interferons. Using MCMV mutants lacking M27 and mice lacking STAT2, we studied the opposing relationship between antiviral activities and viral antagonism in a natural host-pathogen pair in vitro and in vivo In contrast to wt-MCMV, ΔM27-MCMV was efficiently cleared from all organs within a few days in BALB/c, C57BL/6, and 129 mice, highlighting the general importance of STAT2 antagonism for MCMV replication...
May 9, 2018: Journal of Virology
Shun Chen, Chao Yang, Wei Zhang, Suresh Mahalingam, Mingshu Wang, Anchun Cheng
Infections with viruses in the Flaviviridae family have a vast global and economic impact because of the high morbidity and mortality. The pathogenesis of Flaviviridae infections is very complex and not fully understood because these viruses can inhibit multiple immune pathways including the complement system, NK cells, and IFN induction and signalling pathways. The non-structural (NS) 5 and 5A proteins of Flaviviridae viruses are highly conserved and play an important role in resisting host immunity through various evasion mechanisms...
May 6, 2018: Pharmacology & Therapeutics
Ge Guan, Yuntai Shen, Qianqian Yu, Huan Liu, Bin Zhang, Yuan Guo, Xiaodan Zhu, Zhiqiang Li, Wei Rao, Likun Zhuang, Yunjin Zang
Hepatic ischemia-reperfusion injury (IRI) could result in severe liver damage and dysfunction during liver surgery and transplantation. As one of the Interferon (IFN)-stimulated genes, IFIT3 exerted antitumor activity but its roles in hepatic IRI are still unknown. In this study, roles of IFIT3 in hepatic IRI were investigated using a mouse hepatic IRI model and a cellular hypoxia-reoxygenation model. Firstly, our results showed that IFIT3 was up-regulated in reperfused liver tissues of patients undergoing liver transplantation and was positively correlated with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)...
May 4, 2018: International Immunopharmacology
X Z Liu, Y Gao, C H Zhu, K Qi, X Xu, D B Zhao
Objective: To investigate if Dishevelled 2 (DVL2) regulates the apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) via the JAK-STAT pathway. Methods: DVL2 overexpressed lentivirus was transfected into RA-FLS and the apoptosis rate was detected by flow cytometry. The effect of DVL2 on RA-FLS signaling pathway was detected by RNA-seq, and then the key genes were verified by RT-PCR. Results: Compared with the control group, DVL2 significantly increased the apoptosis rate of MH7A (3.2%±2.2% vs 25...
April 17, 2018: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Ida Lindström, Jakob Dogan
Intrinsically disordered proteins (IDPs) are abundant in the eukaryotic proteome. However, little is known about the role of subnanosecond dynamics and the conformational entropy that it represents in protein-protein interactions involving IDPs. Using nuclear magnetic resonance side chain and backbone relaxation, stopped-flow kinetics, isothermal titration calorimetry, and computational studies, we have characterized the interaction between the globular TAZ1 domain of the CREB binding protein and the intrinsically disordered transactivation domain of STAT2 (TAD-STAT2)...
May 18, 2018: ACS Chemical Biology
Jing Nan, Yuxin Wang, Jinbo Yang, George R Stark
In response to IFNβ, the IL6 gene is activated, modestly at early times by ISGF3 (IRF9 plus tyrosine-phosphorylated STATs 1 and 2), and strongly at late times by U-ISGF3 (IRF9 plus U-STATs 1 and 2, lacking tyrosine phosphorylation). A classical IFN-stimulated response element (ISRE) at -1,513 to -1,526 in the human IL6 promoter is required. Pretreating cells with IFNβ or increasing the expression of U-STAT2 and IRF9 exogenously greatly enhances IL6 expression in response to the classical NF-κB activators IL1, TNF, and LPS...
April 10, 2018: Proceedings of the National Academy of Sciences of the United States of America
Siobhan Gargan, Suaad Ahmed, Rebecca Mahony, Ciaran Bannan, Silvia Napoletano, Cliona O'Farrelly, Persephone Borrow, Colm Bergin, Nigel J Stevenson
Anti-retroviral therapy successfully suppresses HIV-1 infection, but fails to provide a cure. During infection Type 1 IFNs normally play an essential role in viral clearance, but in vivo IFN-α only has a modest impact on HIV-1 infection, suggesting its possible targeting by HIV. Here, we report that the HIV protein, Vif, inhibits effective IFN-α signalling via degradation of essential JAK/STAT pathway components. We found that STAT1 and STAT3 are specifically reduced in HEK293T cells expressing Vif and that full length, infectious HIV-1 IIIB strain promotes their degradation in a Vif-dependent manner...
April 2018: EBioMedicine
Jonny Hertzog, Antonio Gregorio Dias Junior, Rachel E Rigby, Claire L Donald, Alice Mayer, Erdinc Sezgin, Chaojun Song, Boquan Jin, Philip Hublitz, Christian Eggeling, Alain Kohl, Jan Rehwinkel
Zika virus (ZIKV) is a major public health concern in the Americas. We report that ZIKV infection and RNA extracted from ZIKV infected cells potently activated the induction of type I interferons (IFNs). This effect was fully dependent on the mitochondrial antiviral signaling protein (MAVS), implicating RIG-I-like receptors (RLRs) as upstream sensors of viral RNA. Indeed, RIG-I and the related RNA sensor MDA5 contributed to type I IFN induction in response to RNA from infected cells. We found that ZIKV NS5 from a recent Brazilian isolate blocked type I IFN induction downstream of RLRs and also inhibited type I IFN receptor (IFNAR) signaling...
March 23, 2018: European Journal of Immunology
J-H Kang, E-A Lee, K-C Hong, J-M Kim
Among swine reproductive traits, sow lifetime productivity (SLP) is considered a profitable trait in commercial pig farming. Notably, longevity and efficiency in SLP can be adopted as the key phenotype representing SLP. In this study, we conducted a co-association network analysis using results from a genome-wide association study for SLP-related traits. A total of 656 purebred Landrace female pigs were genotyped using a 60K SNP array. Significantly associated SNPs identified from the GWAS were annotated for the specific genes...
March 23, 2018: Animal Genetics
Raquel Portugal, Alexandre Leitão, Carlos Martins
ASFV causes an important disease of domestic swine and wild boar. Currently no vaccine is available, highlighting the necessity to understand ASFV modulation of innate immune responses in natural host cells. With this aim, macrophage cultures enriched in SWC9 and CD163 differentiation markers were infected in parallel with high virulent ASFV/L60 and low virulent ASFV/NHV, the latter lacking MGF 360 and 505/530 genes associated with type I interferon (IFN I) control. IFN I production and signaling were studied after completion of the viral cycles...
March 2018: Veterinary Microbiology
Lara A Aqrawi, Janicke Liaaen Jensen, Gunnvor Øijordsbakken, Ann-Kristin Ruus, Ståle Nygård, Marit Holden, Roland Jonsson, Hilde Kanli Galtung, Kathrine Skarstein
A characteristic feature of primary Sjögren's syndrome (pSS) is the destruction of salivary and lacrimal glands mediated by mononuclear cell infiltration. Adipocytes can also occupy a large portion of the salivary gland (SG) tissue area, although little is known about their significance in pSS. We have previously investigated adipose tissue infiltration in SG biopsies from pSS patients and non-SS sicca controls. Our findings indicated the distinct incidence of adipose tissue replacement in pSS patients, where adipocytes were detected in interleukin (IL) 6 rich regions...
May 2018: Autoimmunity
Anja Schöbel, Kathrin Rösch, Eva Herker
Knowledge of activation and interplay between the hepatitis C virus (HCV) and the hosts' innate immunity is essential to understanding the establishment of chronic HCV infection. Human hepatoma cell lines, widely used as HCV cell culture system, display numerous metabolic alterations and a defective innate immunity, hindering the detailed study of virus-host interactions. Here, we analysed the suitability of induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) as a physiologically relevant model to study HCV replication in vitro...
March 1, 2018: Scientific Reports
Alecia Seliga, Michael Hweemoon Lee, Nicole C Fernandes, Viviana Zuluaga-Ramirez, Marta Didukh, Yuri Persidsky, Raghava Potula, Stefania Gallucci, Uma Sriram
The Kallikrein-Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin-converting enzyme (ACE), and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand), or recombinant IFN-α to induce interferon-stimulated genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein), or captopril (an ACE inhibitor)...
2018: Frontiers in Immunology
Oded Danziger, Tal Pupko, Eran Bacharach, Marcelo Ehrlich
Malignancy-induced alterations to cytokine signaling in tumor cells differentially regulate their interactions with the immune system and oncolytic viruses. The abundance of inflammatory cytokines in the tumor microenvironment suggests that such signaling plays key roles in tumor development and therapy efficacy. The JAK-STAT axis transduces signals of interleukin-6 (IL-6) and interferons (IFNs), mediates antiviral responses, and is frequently altered in prostate cancer (PCa) cells. However, how activation of JAK-STAT signaling with different cytokines regulates interactions between oncolytic viruses and PCa cells is not known...
2018: Frontiers in Immunology
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