scholarly journals West Nile Virus Nonstructural Protein 1 Inhibits TLR3 Signal Transduction

2008 ◽  
Vol 82 (17) ◽  
pp. 8262-8271 ◽  
Author(s):  
Jason R. Wilson ◽  
Paola Florez de Sessions ◽  
Megan A. Leon ◽  
Frank Scholle
Keyword(s):  
Signal Transduction ◽  
Immune Response ◽  
West Nile Virus ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Innate Immune ◽  
Productive Infection ◽  
West Nile ◽  
Antiviral State ◽  
Nonstructural Protein 1

ABSTRACT The innate immune response is the first line of defense against foreign pathogens. The recognition of virus-associated molecular patterns, including double- and single-stranded RNA, by pattern recognition receptors initiates a cascade of signaling reactions. These result in the transcriptional upregulation and secretion of proinflammatory cytokines that induce an antiviral state. Many viruses have evolved mechanisms to antagonize these responses in order to help them establish a productive infection. We have previously shown that West Nile virus (WNV) is able to inhibit Toll-like receptor 3 (TLR3)-mediated activation of interferon (IFN) regulatory factor 3 (IRF3) (F. Scholle and P. W. Mason, Virology 342:77-87, 2005). In the present study, the WNV nonstructural (NS) proteins were analyzed individually for their ability to antagonize signal transduction mediated by TLR3. We report that expression of WNV NS1 inhibits TLR3-induced transcriptional activation of the IFN-β promoter and of an NF-κB-responsive promoter. This inhibition was due to a failure of the TLR3 ligand poly(I:C) to induce nuclear translocation of IRF3 and NF-κB. Furthermore, NS1 expression also inhibited TLR3-dependent production of interleukin-6 and the establishment of an antiviral state. The function of NS1 in flavivirus infection is not well understood. NS1 is required for viral RNA replication and is also secreted from mammalian cells but not from insect cells. Here, we identify a previously unrecognized role for NS1 in the modulation of signaling pathways of the innate immune response to WNV infection.

scholarly journals The early protective innate immune response against West Nile virus

2008 ◽  
Vol 2 (S1) ◽  
Author(s):  
Stephane Daffis ◽  
Melanie A Samuel ◽  
Mehul S Suthar ◽  
Brian K Keller ◽  
Michael Gale ◽  
...  
Keyword(s):  
Immune Response ◽  
West Nile Virus ◽  
Innate Immune Response ◽  
Innate Immune ◽  
West Nile

scholarly journals Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly

2008 ◽  
Vol 82 (15) ◽  
pp. 7613-7623 ◽  
Author(s):  
Kok-Fai Kong ◽  
Karine Delroux ◽  
Xiaomei Wang ◽  
Feng Qian ◽  
Alvaro Arjona ◽  
...  
Keyword(s):  
Immune Response ◽  
West Nile Virus ◽  
Innate Immune Response ◽  
The Elderly ◽  
Innate Immune ◽  
Intercellular Adhesion Molecule ◽  
Older Individuals ◽  
West Nile ◽  
Cytokine Levels

ABSTRACT West Nile virus (WNV), a mosquito-borne flavivirus, has recently emerged in North America, and the elderly are particularly susceptible to severe neurological disease and death from infection with this virus. We have investigated the innate immune response of primary human macrophages to WNV in vitro and have found significant differences between the responsiveness of macrophages derived from younger donors and that from older donors. Binding of the glycosylated WNV envelope protein to the C-type lectin dendritic cell-specific intercellular adhesion molecule 3 (ICAM3) grabbing nonintegrin (DC-SIGN) leads to a reduction in the expression of Toll-like receptor 3 (TLR3) in macrophages from young donors via the signal transducer and activator of transcription 1 (STAT1)-mediated pathway. This signaling is impaired in the elderly, and the elevated levels of TLR3 result in an elevation of cytokine levels. This alteration of the innate immune response with aging may contribute to the permeability of the blood-brain barrier and suggests a possible mechanism for the increased severity of WNV infection in older individuals.

Characterization of non-lethal West Nile Virus (WNV) infection in horses: Subclinical pathology and innate immune response

2017 ◽  
Vol 103 ◽  
pp. 71-79 ◽  
Author(s):  
Helle Bielefeldt-Ohmann ◽  
Angela Bosco-Lauth ◽  
Airn-Elizabeth Hartwig ◽  
M. Jasim Uddin ◽  
Jean Barcelon ◽  
...  
Keyword(s):  
Immune Response ◽  
West Nile Virus ◽  
Innate Immune Response ◽  
Innate Immune ◽  
West Nile

scholarly journals The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance

2018 ◽  
Author(s):  
Leeanna El-Houjeiri ◽  
Elite Possik ◽  
Tarika Vijayaraghavan ◽  
Mathieu Paquette ◽  
José A Martina ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Pathogen Resistance ◽  
Innate Immune ◽  
Negative Regulator ◽  
Energy Status ◽  
Rapid Reduction ◽  
Coupling Energy ◽  
Mtorc1 Signaling

AbstractTFEB and TFE3 are transcriptional regulators of the innate immune response, but the mechanisms regulating their activation upon pathogen infection are poorly elucidated. UsingC. elegansand mammalian models, we report that the master metabolic modulator 5’-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN) act upstream of TFEB/TFE3 in the innate immune response, independently of the mTORC1 signaling pathway. In nematodes, loss of FLCN or overexpression of AMPK conferred pathogen resistanceviaactivation of TFEB/TFE3-dependent antimicrobial genes, while ablation of total AMPK activity abolished this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPK induced TFEB/TFE3-dependent pro-inflammatory cytokine expression. Importantly, a rapid reduction in cellular ATP levels in murine macrophages was observed upon lipopolysaccharide (LPS) treatment accompanied by an acute AMPK activation and TFEB nuclear localization. These results uncover an ancient, highly conserved and pharmacologically actionable mechanism coupling energy status with innate immunity.

Role of miRNA-146a in the regulation of the innate immune response and cancer

2008 ◽  
Vol 36 (6) ◽  
pp. 1211-1215 ◽  
Author(s):  
Andrew E. Williams ◽  
Mark M. Perry ◽  
Sterghios A. Moschos ◽  
Hanna M. Larner-Svensson ◽  
Mark A. Lindsay
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Mrna Translation ◽  
Nuclear Factor Κb ◽  
Causal Link ◽  
Innate Immune ◽  
Major Function ◽  
Biological Responses

In mammalian cells, miRNAs (microRNAs) are the most abundant family of small non-coding RNAs that regulate mRNA translation through the RNA interference pathway. In general, it appears that the major function of miRNAs is in development, differentiation and homoeostasis, which is indicated by studies showing aberrant miRNA expression during the development of cancer. Interestingly, changes in the expression of miR-146a have been implicated in both the development of multiple cancers and in the negative regulation of inflammation induced via the innate immune response. Furthermore, miR-146a expression is driven by the transcription factor NF-κB (nuclear factor κB), which has been implicated as an important causal link between inflammation and carcinogenesis. In the present article, we review the evidence for a role of miR-146a in innate immunity and cancer and assess whether changes in miR-146a might link these two biological responses.

Cytotoxicity of, and innate immune response to, size-controlled polypyrrole nanoparticles in mammalian cells

Biomaterials ◽  
2011 ◽  
Vol 32 (9) ◽  
pp. 2342-2350 ◽  
Author(s):  
Sojin Kim ◽  
Wan-Kyu Oh ◽  
Yoon Seon Jeong ◽  
Jin-Yong Hong ◽  
Bo-Ram Cho ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Innate Immune ◽  
Polypyrrole Nanoparticles ◽  
Size Controlled

scholarly journals MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis

2016 ◽  
Vol 90 (16) ◽  
pp. 7098-7108 ◽  
Author(s):  
Jincun Zhao ◽  
Rahul Vijay ◽  
Jingxian Zhao ◽  
Michael Gale ◽  
Michael S. Diamond ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
West Nile Virus ◽  
Hematopoietic Cells ◽  
The United States ◽  
Innate Immune ◽  
Target Cells ◽  
West Nile ◽  
Adaptor Molecule ◽  
The Brain

ABSTRACTWest Nile virus (WNV) is the most important cause of epidemic encephalitis in North America. Innate immune responses, which are critical for control of WNV infection, are initiated by signaling through pathogen recognition receptors, RIG-I and MDA5, and their downstream adaptor molecule, MAVS. Here, we show that a deficiency of MAVS in hematopoietic cells resulted in increased mortality and delayed WNV clearance from the brain. InMavs−/−mice, a dysregulated immune response was detected, characterized by a massive influx of macrophages and virus-specific T cells into the infected brain. These T cells were polyfunctional and lysed peptide-pulsed target cellsin vitro. However, virus-specific T cells in the brains of infectedMavs−/−mice exhibited lower functional avidity than those in wild-type animals, and even virus-specific memory T cells generated by prior immunization could not protectMavs−/−mice from WNV-induced lethal disease. Concomitant with ineffective virus clearance, macrophage numbers were increased in theMavs−/−brain, and both macrophages and microglia exhibited an activated phenotype. Microarray analyses of leukocytes in the infectedMavs−/−brain showed a preferential expression of genes associated with activation and inflammation. Together, these results demonstrate a critical role for MAVS in hematopoietic cells in augmenting the kinetics of WNV clearance and thereby preventing a dysregulated and pathogenic immune response.IMPORTANCEWest Nile virus (WNV) is the most important cause of mosquito-transmitted encephalitis in the United States. The innate immune response is known to be critical for protection in infected mice. Here, we show that expression of MAVS, a key adaptor molecule in the RIG-I-like receptor RNA-sensing pathway, in hematopoietic cells is critical for protection from lethal WNV infection. In the absence of MAVS, there is a massive infiltration of myeloid cells and virus-specific T cells into the brain and overexuberant production of proinflammatory cytokines. These results demonstrate the important role that MAVS expression in hematopoietic cells has in regulating the inflammatory response in the WNV-infected brain.

Sign in / Sign up

Export Citation Format

Share Document