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Temet M McMichael, Yu Zhang, Adam D Kenney, Lizhi Zhang, Ashley Zani, Mijia Lu, Mahesh Chemudupati, Jianrong Li, Jacob S Yount
Human metapneumovirus (hMPV) utilizes a bifurcated cellular entry strategy, fusing either with the plasma membrane or, after endocytosis, with the endosome membrane. Whether cellular factors restrict or enhance either entry pathway is largely unknown. We found that the interferon-induced transmembrane protein 3 (IFITM3) inhibits hMPV infection to an extent similar to endocytosis-inhibiting drugs, and an IFITM3 variant that accumulates at the plasma membrane in addition to its endosome localization provided increased virus restriction...
June 15, 2018: Journal of Infectious Diseases
Artur Javmen, Henryk Szmacinski, Joseph R Lakowicz, Vladimir Y Toshchakov
Interaction of TLR9 with ligands activates NF-κB, leading to proinflammatory cytokine production. Excessive TLR activation is a pathogenic factor for inflammatory diseases. This study has examined cell-permeating decoy peptides (CPDPs) derived from the TLR9 Toll/IL-1R resistance (TIR) domain. CPDP 9R34, which included AB loop, β-strand B, and N-terminal BB loop residues, inhibited TLR9 signaling most potently. CPDPs derived from α-helices C, D, and E (i.e., 9R6, 9R9, and 9R11) also inhibited TLR9-induced cytokines but were less potent than 9R34...
June 18, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Yue Wu, Tingzheng Liu, Yuhang Yuan, Zhibo Zhang
PURPOSE: To identify genes potentially involved in the pathogenesis of bile duct obstruction in biliary atresia (BA). METHODS: We used rhesus rotavirus (RRV) Balb/c mouse BA model to study BA. Liver and serum samples were harvested from BA and normal control (NC) groups at 1, 3, 5, 7, 10 and 14 days postinoculation. Serum total bilirubin (STB) and conjugated bilirubin (CB) were measured. Livers of each group at day 7 were used for a genome-wide expression analysis...
June 14, 2018: Biochemical and Biophysical Research Communications
Baptiste Lamarthée, Frédéric de Vassoigne, Florent Malard, Nicolas Stocker, Inès Boussen, Clémence Médiavilla, Ruoping Tang, Fanny Fava, Laurent Garderet, Zora Marjanovic, Eolia Brissot, Mohamad Mohty, Béatrice Gaugler
Multiple myeloma (MM) results from expansion of abnormal plasma cells in the bone marrow (BM). Previous studies have shown that monocytes play a crucial role in MM pathophysiology. A 6-sulfo LacNAc-expressing population of dendritic cells (Slan-DCs) that overlaps with intermediate and non-classical monocytes in terms of phenotype has been described. Slan-DCs represent a circulating and tissue proinflammatory myeloid population which has been shown to play a role in different cancer contexts, and which exhibits a remarkable plasticity...
2018: Oncoimmunology
Mayuresh M Abhyankar, Mark T Orr, Susan Lin, Mohammed O Suraju, Adrian Simpson, Molly Blust, Tiep Pham, Jeffrey A Guderian, Mark A Tomai, James Elvecrog, Karl Pedersen, William A Petri, Christopher B Fox
Amebiasis caused by Entamoeba histolytic a is the third leading cause of parasitic mortality globally, with some 100,000 deaths annually, primarily among young children. Protective immunity to amebiasis is associated with fecal IgA and IFN-γ in humans; however, no vaccine exists. We have previously identified recombinant LecA as a potential protective vaccine antigen. Here we describe the development of a stable, manufacturable PEGylated liposomal adjuvant formulation containing two synthetic Toll-like receptor (TLR) ligands: GLA (TLR4) and 3M-052 (TLR7/8)...
2018: NPJ Vaccines
Cristina Cappelletti, Franco Salerno, Eleonora Canioni, Marina Mora, Renato Mantegazza, Pia Bernasconi, Lorenzo Maggi
Laminopathies are a heterogeneous group of diseases with overlapping phenotypes that are caused by mutations in the nuclear envelope proteins lamin A and C. The most common group of laminopathies affects skeletal and cardiac muscle tissue, and is defined as LMNA-related myopathies (LMNA-RM). In LMNA-RM patients, muscle histological findings are very variable, ranging from mild and unspecific changes to dystrophic features, sometimes with inflammatory evidence. As recently demonstrated in Duchenne muscular dystrophy, we wondered whether in LMNA-RM muscle tissue the genetic defect might determine the activation of an innate immune response, mainly mediated by Toll-like receptors (TLRs), leading to a chronic inflammation and contributing to myofiber necrosis and fibrosis...
June 12, 2018: Nucleus
Hana Velová, Maria W Gutowska-Ding, David W Burt, Michal Vinkler
Toll-like receptors (TLRs) are key sensor molecules in vertebrates triggering initial phases of immune responses to pathogens. The avian TLR family typically consists of ten receptors, each adapted to distinct ligands. To understand the complex evolutionary history of each avian TLR, we analysed all members of the TLR family in the whole genome assemblies and target sequence data of 63 bird species covering all major avian clades. Our results indicate that gene duplication events most probably occurred in TLR1 before synapsids diversified from sauropsids...
June 8, 2018: Molecular Biology and Evolution
Purvi Mande, Bahar Zirak, Wei-Che Ko, Keyon Taravati, Karen L Bride, Tia Y Brodeur, April Deng, Karen Dresser, Zhaozhao Jiang, Rachel Ettinger, Katherine A Fitzgerald, Michael D Rosenblum, John E Harris, Ann Marshak-Rothstein
Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9...
June 11, 2018: Journal of Clinical Investigation
Willem G Coetzer, Trudy R Turner, Christopher A Schmitt, J Paul Grobler
Vervet monkeys ( Chlorocebus pygerythrus ) are one of the most widely distributed non-human primate species found in South Africa. They occur across all the South African provinces, inhabiting a large variety of habitats. These habitats vary sufficiently that it can be assumed that various factors such as pathogen diversity could influence populations in different ways. In turn, these factors could lead to varied levels of selection at specific fitness linked loci. The Toll-like receptor ( TLR ) gene family, which play an integral role in vertebrate innate immunity, is a group of fitness linked loci which has been the focus of much research...
2018: PeerJ
Susanne Maria Ziegler, Cai Niklaas Feldmann, Sven Hendrik Hagen, Laura Richert, Tanja Barkhausen, Janina Goletzke, Virginija Jazbutyte, Gloria Martrus, Wilhelm Salzberger, Thomas Renné, Kurt Hecher, Anke Diemert, Petra Clara Arck, Marcus Altfeld
During pregnancy the maternal immune system has to develop tolerance towards the developing fetus. These changes in maternal immunity can result in increased severity of certain infections, but also in amelioration of autoimmune diseases. Pregnancy-related hormones have been suggested to play a central role in the adaptation of the maternal immune system, but their specific effects on innate immune function is not well understood. In a longitudinal study of pregnant women, we investigated innate immune cell function in response to toll-like receptors (TLR) 4 and 7 stimulation, two TLR pathways playing a critical role in early innate immune recognition of bacteria and viruses...
May 24, 2018: Journal of Reproductive Immunology
Yun-Fen Hung, Chiung-Ya Chen, Wan-Chen Li, Ting-Fang Wang, Yi-Ping Hsueh
The neuronal innate immune system recognizes endogenous danger signals and regulates neuronal development and function. Toll-like receptor 7 (TLR7), one of the TLRs that trigger innate immune responses in neurons, controls neuronal morphology. To further assess the function of TLR7 in the brain, we applied next generation sequencing to investigate the effect of Tlr7 deletion on gene expression in hippocampal and cortical mixed cultures and on mouse behaviors. Since previous in vivo study suggested that TLR7 is more critical for neuronal morphology at earlier developmental stages, we analyzed two time-points (4 and 18 DIV) to represent young and mature neurons, respectively...
June 7, 2018: Brain, Behavior, and Immunity
Sonya J Wolf, Jonathan Theros, Tammi J Reed, Jianhua Liu, Irina L Grigorova, Giovanny Martínez-Colón, Chaim O Jacob, Jeffrey B Hodgin, J Michelle Kahlenberg
Systemic lupus erythematosus is an autoimmune disease characterized by increased type I IFNs, autoantibodies, and inflammatory-mediated multiorgan damage. TLR7 activation is an important contributor to systemic lupus erythematosus pathogenesis, but the mechanisms by which type I IFNs participate in TLR7-driven pathologic conditions remain uncertain. In this study, we examined the requirement for type I IFNs in TLR7-stimulated lupus nephritis. Lupus-prone NZM2328, INZM (which lack a functional type I IFN receptor), and NZM2328 IL-1β-/- mice were treated at 10 wk of age on the right ear with R848 (TLR7 agonist) or control (DMSO)...
June 8, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Rushit N Lodaya, Luis A Brito, Tom Y H Wu, Andrew T Miller, Gillis R Otten, Manmohan Singh, Derek T O'Hagan
Adjuvants are required to enhance immune responses to typically poorly immunogenic recombinant antigens. Toll like receptor agonists (TLRa) have been widely evaluated as adjuvants, since they activate the innate immune system. Currently, licensed vaccines adjuvanted with TLRa include the TLR4 agonist Monophosphoryl Lipid (MPL), while additional TLRa are in clinical development. Unfortunately, naturally derived TLRa are often complex and heterogeneous entities, which brings formulation challenges. Consequently, the use of synthetic small molecule TLRa has significant advantages, since they are well-defined discreet molecules, which can be chemically modified to modulate their physicochemical properties...
June 5, 2018: Journal of Pharmaceutical Sciences
Lucas L van den Hoogen, Marzia Rossato, Ana P Lopes, Aridaman Pandit, Cornelis P J Bekker, Ruth D E Fritsch-Stork, Joel A G van Roon, Timothy R D J Radstake
Objective: To investigate miRNA expression in relation to transcriptomic changes in plasmacytoid dendritic cells (pDCs) in SLE and APS. pDCs are major producers of IFNα in SLE and APS, and miRNAs are emerging as regulators of pDC activation. Methods: miRNA and mRNA expression were measured by OpenArray and RNA-sequencing in pDCs of SLE, SLE + APS (APS secondary to SLE) and primary APS (PAPS) patients. The miRNA profile of patients was compared with the miRNA pattern of TLR7-activated pDCs...
June 4, 2018: Rheumatology
Qingsong Lei, Lin Li, Shujun Zhang, Tianju Li, Xiaomei Zhang, Xiaolin Ding, Bo Qin
Hepatitis E is the most common type of acute hepatitis prevalent worldwide. The open reading frame 3 protein of HEV (HEV ORF3) is proposed to create a favorable environment for viral replication and pathogenesis. However, the mechanisms by which HEV overcomes the effects of host immunity, particularly the role of ORF3, remain to be established. Expression of IFNα and IFNβ in supernatant and cell samples was examined via ELISA and quantitative RT-PCR. The protein levels of specific signaling factors in cells overexpressing HEV ORF3 were examined via western blot...
June 5, 2018: Scientific Reports
Casper Marsman, Fanny Lafouresse, Yang Liao, Tracey M Baldwin, Lisa A Mielke, Yifang Hu, Matthias Mack, Paul J Hertzog, Carolyn A de Graaf, Wei Shi, Joanna R Groom
Plasmacytoid dendritic cells (pDCs) play a critical role in bridging the innate and adaptive immune systems. pDCs are specialized type I interferon (IFN) producers, which has implicated them as initiators of autoimmune pathogenesis. However, little is known about the down-stream effectors of type I IFN signaling that amplify autoimmune responses. Here we have used a chemokine reporter mouse to determine the CXCR3 ligand responses in DCs subsets. Following TLR7 stimulation conventional type 1 and type 2 DCs (cDC1 and cDC2 respectively) uniformly upregulate CXCL10...
June 5, 2018: Immunology and Cell Biology
Ming-Xing Wang, Jing-Xia Zhao, Yu-Jiao Meng, Ting-Ting Di, Xiao-Long Xu, Xiang-Jiang Xie, Yan Lin, Lu Zhang, Ning Wang, Ping Li, Yan Wang
AIMS: Psoriasis vulgaris is mediated by T and dendritic cells. This study aimed to investigate the effects of acetyl-11-keto-β-boswellic acid (AKBA) on activated dendritic cells (DCs) using an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow-derived dendritic cells (BMDCs) stimulated with resiquimod (R848) in vitro. MATERIALS AND METHODS: The mice were treated with IMQ and intragastrically administered 25-100 mg/kg/day of AKBA, 1 mg/kg/day of methotrexate (MTX), or normal saline...
May 30, 2018: Life Sciences
Alex C D Salyer, Sunil A David
An important component of vaccine development is the identification of safe and effective adjuvants. We sought to identify transcriptomal signatures of innate immune stimulating molecules using next-generation RNA sequencing with the goal of being able to utilize such signatures in identifying novel immunostimulatory compounds with adjuvant activity. The CC family of chemokines, particularly CC chemokines 1, 2, 3, 4, 7, 8, 17, 18, 20, and 23, were broadly upregulated by most Toll-like receptor (TLR) and nucleotide-binding domain and leucine-rich repeat-containing receptors (NLR) stimuli...
May 31, 2018: Human Vaccines & Immunotherapeutics
Hong-Qiong Qin, Shan-Shan Shi, Ying-Jie Fu, Yu-Qi Yan, Sha Wu, Xiao-Long Tang, Xiao-Yin Chen, Guang-Hui Hou, Zhen-You Jiang
Objective: We wished to investigate the effects of the traditional Chinese medicine Gui Zhi Ma Huang Ge Ban Tang on controlling influenza A virus (IAV) infection and improving inflammation in mouse lungs. Method: Mice were maintained in normal and cold environments and infected with IAV by intranasal application, respectively. Real-time quantitative polymerase chain reaction was used to measure mRNA expression of TLR7, myeloid differentiation primary response 88 (MyD88), and nuclear factor-kappa B (NF- κ B)p65 in the TLR7 signaling pathway and virus replication in lungs...
2018: Evidence-based Complementary and Alternative Medicine: ECAM
Agnieszka Kloch, Marius A Wenzel, Dominik R Laetsch, Olek Michalski, Renata Welc-Falęciak, Stuart B Piertney
Selective pressure from pathogens is considered a key selective force driving the evolution of components of the immune system. Since single components of the immune system may interact with many pathogens, and single pathogens may be recognized by multiple components of the immune system, gaining a better understanding of the mechanisms of parasite-driven selection requires the study of multiple genes and pathogens. Toll-like receptors (TLRs) are a large gene family that code for antigen-presenting components of the innate immune response...
May 30, 2018: Scientific Reports
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