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Jarrod S Johnson, Sasha Y Lucas, Lynn M Amon, Stephanie Skelton, Rodolfo Nazitto, Sara Carbonetti, D Noah Sather, Dan R Littman, Alan Aderem
Myeloid dendritic cells (DCs) have the innate capacity to sense pathogens and orchestrate immune responses. However, DCs do not mount efficient immune responses to HIV-1, primarily due to restriction of virus reverse transcription, which prevents accumulation of viral cDNA and limits its detection through the cGAS-STING pathway. By allowing reverse transcription to proceed, we find that DCs detect HIV-1 in distinct phases, before and after virus integration. Blocking integration suppresses, but does not abolish, activation of the transcription factor IRF3, downstream interferon (IFN) responses, and DC maturation...
March 14, 2018: Cell Host & Microbe
Peter Moritz Becher, Svenja Hinrichs, Nina Fluschnik, Jan K Hennigs, Karin Klingel, Stefan Blankenberg, Dirk Westermann, Diana Lindner
Heart failure (HF) is a leading cause of morbidity and mortality in the western world. Although optimal medical care and treatment is widely available, the prognosis of patients with HF is still poor. Toll-like receptors (TLRs) are important compartments of the innate immunity. Current studies have identified TLRs as critical mediators in cardiovascular diseases. In the present study, we investigated the involvement of TLRs and interferon (IFN) regulatory factors (IRFs) in different experimental HF models including viral myocarditis, myocardial ischemia, diabetes mellitus, and cardiac hypertrophy...
2018: PloS One
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
Ah-Yeon Kim, Hyun-Jin Shim, Hyeon-Myeong Shin, Yoo Jung Lee, Hyeonjeong Nam, Su Yeon Kim, Hyung-Sun Youn
Toll-like receptors (TLRs) play a crucial role in danger recognition and induction of innate immune response against bacterial and viral infections. The TLR adaptor molecule, toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF), facilitates TLR3 and TLR4 signaling, leading to the activation of the transcription factor, NF-κB and interferon regulatory factor 3 (IRF3). Andrographolide, the active component of Andrographis paniculata, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear...
March 1, 2018: International Immunopharmacology
Le Guo, Xi-Qiu Xu, Li Zhou, Run-Hong Zhou, Xu Wang, Jie-Liang Li, Jin-Biao Liu, Hang Liu, Biao Zhang, Wen-Zhe Ho
As a rich source of CD4+ T cells and macrophages, the gastrointestinal (GI) tract is a major target site for HIV infection. The interplay between GI-resident macrophages and intestinal epithelial cells (IECs) constitutes an important element of GI innate immunity against pathogens. In this study, we investigated whether human IECs have the ability to produce antiviral factors that can inhibit HIV infection of macrophages. We demonstrated that IECs possess functional toll-like receptor 3 (TLR3), the activation of which resulted in induction of key interferon (IFN) regulatory factors (IRF3 and IRF7), IFN-β, IFN-λ, and CC chemokines (MIP-1α, MIP-1β, RANTES), the ligands of HIV entry co-receptor CCR5...
2018: Frontiers in Immunology
Tate Tabtieng, Alexei Degterev, Marta M Gaglia
An important component of lytic infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is the ability of the virus to evade the innate immune response, specifically type I interferon (IFN) responses that are triggered by recognition of viral nucleic acids. Inhibition of type I IFN responses by the virus promotes viral replication. Here we report that KSHV uses a caspase-dependent mechanism to block type I IFN, in particular IFNβ, responses during lytic infection. Inhibition of caspases during KSHV reactivation resulted in increased TBK1/IKKϵ-dependent phosphorylation of IRF3 as well as elevated levels of IFNβ transcription and secretion...
March 7, 2018: Journal of Virology
Jun Yang, Chaojun Yang, Jian Yang, Jiawang Ding, Xinxin Li, Qinqin Yu, Xin Guo, Zhixing Fan, Huibo Wang
The Toll-like receptor 4 (TLR4) signal pathway- induced inflammation is considered to be a crucial link to myocardial ischemia reperfusion injury (MIRI). Our previous study proved that radioprotective 105 kDa protein (RP105), a negative regulator of TLR4, performed a protective role in MIRI by anti-apoptosis approach. However, the mechanism of RP105 cardioprotection of anti-inflammation is still unclear. This study aimed to explore the underlying mechanism of RP105 anti-inflammation effect in MIRI. We established a rat model of MIRI induced by ligation of the left anterior descending coronary artery for 30 min followed by 2 h reperfusion...
March 6, 2018: International Journal of Molecular Medicine
Liang Yi, Dan Sun, Qian Han, Zhonghui Liu, Zeng Zeng, Yanping Wu, Xiaoyu Chai, Xinmin Liu
Immunotherapy is considered one of the most promising treatments for lung cancer. The cell signalling molecules melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I protein (RIG‑I) are essential receptors that recognise intracellular pathogen-associated nucleic acids, whereas interferon regulatory factor 3 (IRF3) controls the expression of innate immunity-associated genes in macrophages. However, the innate immune response to polyinosinic:polycytidylic acid [Poly(I:C)] in lung cancer remains to be elucidated...
March 5, 2018: International Journal of Oncology
Chang Li, Shouwen Du, Mingyao Tian, Yuhang Wang, Jieying Bai, Peng Tan, Wei Liu, Ronglan Yin, Maopeng Wang, Ying Jiang, Yi Li, Na Zhu, Yilong Zhu, Tiyuan Li, Shipin Wu, Ningyi Jin, Fuchu He
Interferons (IFNs) establish dynamic host defense mechanisms by inducing various IFN-stimulated genes that encodes many antiviral innate immune effectors. IFN-inducible transmembrane (IFITM) proteins have been identified as intrinsic antiviral effectors, which block the entry of a broad spectrum of enveloped RNA viruses by interrupting virus-endosomal fusion. However, antiviral activity of IFITM proteins against mammalian DNA virus has not been demonstrated till date. Here, we sought to investigate the antiviral activities and mechanisms of interferon-inducible transmembrane protein 3 (IFITM3) protein against poxvirus infection...
2018: Frontiers in Immunology
Hai-Xia Du, Hui-Fen Zhou, Hao-Fang Wan, Jie-Hong Yang, Yi-Yu Lu, Yu He, Hai-Tong Wan
Yinhuapinggan granule (YHPG), a modified prescription based on Ma-Huang-Tang (MHT), is used in traditional Chinese medicine (TCM) to treat influenza, cough, and viral pneumonia. In this study, we investigated the antiviral effects of YHPG by means of pre-, post-, and co-treatment, and its underlying mechanisms on regulating the levels of inflammatory-related cytokines, modulating the mRNA expressions of interferon-stimulated genes in influenza virus-infected murine macrophage cells (RAW264.7), and evaluating the protein expressions of key effectors in the Type I IFN and pattern recognition receptor (PRRs) signaling pathways...
March 3, 2018: Inflammopharmacology
Sayed Masoud Hosseini, Hamid Gholami Pourbadie, Mohammad Sayyah, Mohammad Ismail Zibaii, Nima Naderi
Finding a neuroprotective strategy to rescue patients suffering from acute brain damage is of great interest. Monophosphoryl lipid A (MPL) is a derivative of lipopolysaccharide (LPS) that lacks many of the endotoxic properties of the parent molecule, and yet has similar protective effect. Here, we report the first evidence that MPL preconditioning, similar to LPS preconditioning, can induce neuroprotection against cerebral ischemia. MPL (0.5, 1, 5 µg/rat) was injected unilaterally into the left cerebral ventricle of male rats, and 48h later, rats were subjected to ipsilateral selective hippocampal ischemia using a modified version of the photothrombotic method...
March 1, 2018: Behavioural Brain Research
Kendra A Bussey, Ulrike Lau, Sophie Schumann, Antonio Gallo, Lisa Osbelt, Markus Stempel, Christine Arnold, Josef Wissing, Hans Henrik Gad, Rune Hartmann, Wolfram Brune, Lothar Jänsch, Adrian Whitehouse, Melanie M Brinkmann
Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the few oncogenic human viruses known to date. Its large genome encodes more than 85 proteins and includes both unique viral proteins as well as proteins conserved amongst herpesviruses. KSHV ORF20 is a member of the herpesviral core UL24 family, but the function of ORF20 and its role in the viral life cycle is not well understood. ORF20 encodes three largely uncharacterized isoforms, which we found were localized predominantly in the nuclei and nucleoli...
March 2, 2018: PLoS Pathogens
Thaneas Prabakaran, Chiranjeevi Bodda, Christian Krapp, Bao-Cun Zhang, Maria H Christensen, Chenglong Sun, Line Reinert, Yujia Cai, Søren B Jensen, Morten K Skouboe, Jens R Nyengaard, Craig B Thompson, Robert Jan Lebbink, Ganes C Sen, Geert van Loo, Rikke Nielsen, Masaaki Komatsu, Lene N Nejsum, Martin R Jakobsen, Mads Gyrd-Hansen, Søren R Paludan
Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the second messenger cGAMP, and the adaptor molecule STING Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62-deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens...
March 1, 2018: EMBO Journal
Xiong-Zhe Han, Rui Ma, Qi Chen, Xin Jin, Yuan-Zhe Jin, Ren-Bo An, Xuan-Mei Piao, Mei-Lan Lian, Lin-Hu Quan, Jun Jiang
ETHNOPHARMACOLOGICAL RELEVANCE: The aerial part of Athyrium multidentatum (Doll.) Ching (AM) is widely used in the northeastern region of China as an edible wild herb, but its medicinal value, especially its anti-inflammatory effect, has not been fully explored. AIM OF THE STUDY: To investigate the anti-inflammatory activity of AM and clarify the anti-inflammatory mechanism involving the TLR4 signaling pathway using a lipopolysaccharide (LPS)-induced inflammatory model...
February 21, 2018: Journal of Ethnopharmacology
Sajad Ahmad Wani, Amit Ranjan Sahu, Shikha Saxena, Kaushal Kishor Rajak, M Saminathan, Aditya Prasad Sahoo, Sonam Kanchan, Aruna Pandey, Bina Mishra, D Muthuchelvan, Ashok Kumar Tiwari, Bishnu Prasad Mishra, Raj Kumar Singh, Ravi Kumar Gandham
Here, we studied the in vivo expression of Th1 (IL2 and IFN gamma) and Th2 (IL4 and IL10) - cytokines and antiviral molecules - IRF3 and ISG15 in peripheral blood mononuclear cells in relation to antigen and antibody dynamics under Peste des petits ruminants virus (PPRV) vaccination, infection and challenge in both sheep and goats. Vaccinated goats were seropositive by 9 days post vaccination (dpv) while in sheep idiosyncratic response was observed between 9 and 14 dpv for different animals. Expression of PPRV N gene was not detected in PBMCs of vaccinated and vaccinated challenged groups of both species, but was detected in unvaccinated infected PBMCs at 9 and 14 days post infection...
February 21, 2018: Microbial Pathogenesis
Radiana T Trifonova, Natasha S Barteneva
Imaging flow cytometry (IFC) has become a powerful tool for studying the activation of transcriptional factors in heterogeneous cell populations in high-content imaging mode. With considerable interest to the clinical development of IFC, the question becomes how we can accelerate its application to solid tissues. We developed the first IFC-based procedure to quantify the nuclear translocation of interferon regulatory factor (IRF) 3, an important measure of induction of type I interferon antiviral response, in primary human immune cells including in solid tissues...
2018: Methods in Molecular Biology
Ryo Okada, Xinwen Zhang, Yuka Harada, Zhou Wu, Hiroshi Nakanishi
OBJECTIVE: The objective of this study is to investigate the role of cathepsin H (CatH), a lysosomal cysteine protease, in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. METHODS: EAE was induced in CatH-deficient mice (CatH-/- ) and wild-type littermates (+/+) using myelin oligodendrocyte glycoprotein (MOG) 35-55. The effects of CatH deficiency were determined by clinical scoring, mRNA expression levels of Tbx21, Rorc and FoxP3, protein levels of poly(I:C)-induced toll-like receptor 3 (TLR3) and phosphorylation of IRF3, and secretion of interferon-β (IFN-β) by splenocytes...
February 22, 2018: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Sujatha Muralidharan, Arlene Lim, Donna Catalano, Pranoti Mandrekar
Binge/moderate alcohol suppresses TLR4-MyD88 proinflammatory cytokines; however, alcohol's effects on TLR-TRIF signaling, especially after in vivo exposure in humans, are unclear. We performed a comparative analysis of the TLR4-MyD88, TLR4-TRIF, and TLR3-TRIF pathways in human monocytes following binge alcohol exposure. Mechanistic regulation of TLR-TRIF signaling by binge alcohol was evaluated by analyzing IRF3 and TBK1, upstream regulator protein phosphatase 1 (PP1), and immunoregulatory stress proteins HspA1A and XBP-1 in alcohol-treated human and mouse monocytes/macrophages...
February 14, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Yi Wei Hu, Jie Zhang, Xiao Man Wu, Lu Cao, Pin Nie, Ming Xian Chang
TANK-binding kinase 1 (TBK1) is an important serine/threonine-protein kinase that mediates phosphorylation and nuclear translocation of IRF3, which contributes to induction of type I interferons (IFNs) in the innate antiviral response. In mammals, TBK1 spliced isoform negatively regulates the virus-triggered IFN-β signaling pathway by disrupting the interaction between retinoic acid-inducible gene I (RIG-I) and mitochondria antiviral-signaling protein (MAVS). However, it is still unclear whether alternative splicing patterns and the function of TBK1 isoform(s) exist in teleost fish...
2018: Frontiers in Immunology
Johnasha D Stuart, Geoffrey H Holm, Karl W Boehme
Serotype 3 (T3) reoviruses induce substantially more type 1-interferon (IFN-I) secretion than serotype 1 (T1) strains. However, the mechanisms underlying differences in IFN-I production between T1 and T3 reoviruses remain undefined. Here, we found that differences in IFN-I production between T1 and T3 reoviruses correlates with activation of interferon regulatory factor 3 (IRF3), a key transcription factor for the production of IFN-I. T3 strain rsT3D activated IRF3 more rapidly and to a greater extent than the T1 strain, rsT1L, in SV-40 immortalized endothelial cells (SVECs)...
February 7, 2018: Journal of Virology
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