West Nile Virus Envelope Protein Inhibits dsRNA-Induced Innate Immune Responses

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
The Journal of Immunology (Impact Factor: 4.92). 01/2008; 179(12):8403-9. DOI: 10.4049/jimmunol.179.12.8403
Source: PubMed


The immune response against viral infection relies on the early production of cytokines that induce an antiviral state and trigger the activation of immune cells. This response is initiated by the recognition of virus-associated molecular patterns such as dsRNA, a viral replication intermediate recognized by TLR3 and certain RNA helicases. Infection with West Nile virus (WNV) can lead to lethal encephalitis in susceptible individuals and constitutes an emerging health threat. In this study, we report that WNV envelope protein (WNV-E) specifically blocks the production of antiviral and proinflammatory cytokines induced by dsRNA in murine macrophages. This immunosuppressive effect was not dependent on TLR3 or its adaptor molecule Trif. Instead, our experiments show that WNV-E acts at the level of receptor-interacting protein 1. Our results also indicate that WNV-E requires a certain glycosylation pattern, specifically that of dipteran cells, to inhibit dsRNA-induced cytokine production. In conclusion, these data show that the major structural protein of WNV impairs the innate immune response and suggest that WNV exploits differential vector/host E glycosylation profiles to evade antiviral mechanisms.

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Available from: Yorgo Modis, Oct 07, 2015
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    • "No differences in WNV infectivity were observed in HEK293-TLR3 cells compared to HEK293-Nulls (Figure 1B). This finding is consistent with prior studies [25], [56]. "
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    ABSTRACT: The innate immune response to West Nile virus (WNV) infection involves recognition through toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), leading to establishment of an antiviral state. MiRNAs (miRNAs) have been shown to be reliable biomarkers of TLR activation. Here, we sought to evaluate the contribution of TLR3 and miRNAs to the host response to WNV infection. We first analyzed HEK293-NULL and HEK293-TLR3 cells for changes in the innate immune response to infection. The presence of TLR3 did not seem to affect WNV load, infectivity or phosphorylation of IRF3. Analysis of experimentally validated NFκB-responsive genes revealed a WNV-induced signature largely independent of TLR3. Since miRNAs are involved in viral pathogenesis and the innate response to infection, we sought to identify changes in miRNA expression upon infection in the presence or absence of TLR3. MiRNA profiling revealed 70 miRNAs induced following WNV infection in a TLR3-independent manner. Further analysis of predicted gene targets of WNV signature miRNAs revealed genes highly associated with pathways regulating cell death, viral pathogenesis and immune cell trafficking.
    PLoS ONE 08/2014; 9(8):e104770. DOI:10.1371/journal.pone.0104770 · 3.23 Impact Factor
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    • "WNV E-glycoprotein has been shown to interfere with ubiquitination of RIP-1, a signaling kinase common to both RIG-I and TLR3 pathways, and subvert responses to viral RNA (Arjona et al., 2007). Furthermore, only mosquito cellderived WNV E-glycoprotein showed this subversion, suggesting a plausible immune evasion mechanism during initial infection of the vertebrate host (Arjona et al., 2007). Altogether, these studies reveal the strategies employed by flaviviruses to evade PRR detection and signaling (Fig. 2). "
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    ABSTRACT: The flaviviral encephalitis has now become a major health concern in global scale. The efficient detection of viral infection and induction of the innate antiviral response by host's innate immune system are crucial to determine the outcome of infection. The intracellular pattern recognition receptors TLRs, RLRs, NLRs and CLRs play a central role in detection and initiation of robust antiviral response against flaviviral infection. Both cytoplasmic RLRs, RIG-I and MDA5 have been shown to be implicated in sensing flaviviral genomic RNA. Similarly among TLRs mainly TLR3 and TLR7 are known to respond in flaviviral infections as they are known to sense dsRNA and ssRNA moiety as their natural cognate ligand. Several studies have also shown the roles of NLRs and CLRs in mounting an innate antiviral response against flavivirus but, it is yet to be completely understood. Until now only few reports have implicated NLRs and CLRs in induction of antiviral and proinflammatory state following flaviviral infection. The current review therefore aims to comprehensively analyze past as well as current understanding on the role of PRRs in flaviviral infections.
    Virus Research 06/2014; 185. DOI:10.1016/j.virusres.2014.03.013 · 2.32 Impact Factor
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    • "WNV virions were retained in the plasma membrane and treatment with a proteasomal inhibitor further abolished WNV infection (Krishnan et al., 2008). Furthermore, a WNV envelope protein named WNV-E inhibited dsRNA-induced cytokine production in murine macrophages by altering the pattern of RIP1 ubiquitination and NF-kB activation (Arjona et al., 2007). "
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    ABSTRACT: Ubiquitination (ubiquitylation) is a common protein modification that regulates a multitude of processes within the cell. This modification is typically accomplished through the covalent binding of ubiquitin to a lysine residue onto a target protein and is catalysed by the presence of three enzymes: an activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin-protein ligase (E3). In recent years, ubiquitination has risen as a major signalling regulator of immunity and microbial pathogenesis in the mammalian system. Still, little is known about how ubiquitin relates specifically to vector immunology. Here, we provide a brief overview of ubiquitin biochemistry and describe how ubiquitination regulates immune responses in arthropods of medical relevance. We also discuss scientific gaps in the literature and suggest that, similar to mammals, ubiquitin is a major regulator of immunity in medically important arthropods.
    Cellular Microbiology 07/2013; 15(7). DOI:10.1111/cmi.12128 · 4.92 Impact Factor
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