Toll-Like Receptor 3 Has a Protective Role against West Nile Virus Infection

Abstract

Protection against West Nile virus (WNV) infection requires rapid viralRecent studies have begun to delineate the molecular mechanisms that regulate alpha interferon (IFN-␣) and IFN-␤ induction after infection by RNA and DNA viruses (reviewed in references 13, 24, 25, and 57). Pattern recognition receptors (PRR) sense conserved structural microbial elements identified as pathogen-associated molecular patterns. PRR involved in the recognition of RNA viruses can be divided into two classes. Toll-like receptors (TLR) on the cell surface or within endosomes recognize single-and double-stranded RNA and signal through the adaptor molecules MyD88 and TRIF. In comparison, RIG-I and MDA5 helicases recognize single-and double-stranded RNA in the cytosol and signal through the adaptor protein IPS-1 (also known as MAVS, Cardif, and VISA) (reviewed in references 28, 42, and 55). Recognition by viral RNA sensors results in the downstream activation and nuclear translocation of IRF-3 and IRF-7, which transcriptionally activate IFN-␣ and -␤ gene promoters (46).Cell culture experiments defined TLR3 as a PRR that recognizes double-stranded RNA, activates IRF-3 and NF-B transcriptional pathways, and induces type I IFN (2). The role of TLR3 in vivo in protection against viral infections has been less clear (reviewed in references 5, 36, and 58). Experiments in TLR3Ϫ/Ϫ mice infected with lymphocytic choriomeningitis virus, vesicular stomatitis virus, and reovirus failed to show increased mortality or altered viral burden phenotypes (12). In contrast, TLR3 restricts replication, regulates cytokine production, and protects against infection by mouse cytomegalovirus and encephalomyocarditis virus (EMCV) (21, 54). Indeed, a deficiency in TLR3 in humans was identified as a predisposing genetic risk factor for herpes simplex virus (HSV) encephalitis (61) and influenza A virus-induced encephalopathy (23). An adverse role for TLR3 also has been proposed since TLR3 Ϫ/Ϫ mice infected with influenza, punta toro, and vaccinia viruses showed improved survival and decreased production of inflammatory cytokines (19,26,33). Analogously, conflicting results have been observed with respect to the role of TLR3 in inducing IFN after infection with the encephalitic flavivirus West Nile virus (WNV). TLR3 was largely dispensable for WNV recognition and induction of IFN responses in vitro (15, 47), whereas in mice, an absence of TLR3 protected mice from lethal infection (59). TLR3 Ϫ/Ϫ mice infected via intraperitoneal injection with WNV showed decreased systemic tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) production, blood-brain barrier (BBB) permeability, and infection in the brain.Given this apparent conflict and our previous studies demonstration of an essential role for IRF-3 in controlling WNV infection (6), we reexamined the pathogenesis of virulent WNV infection in TLR3 Ϫ/Ϫ mice. Remarkably, we observed increased susceptibility of TLR3 Ϫ/Ϫ mice to WNV infection. TLR3 had a modest effect on WNV infection in peripheral tissues and was...

A Common Polymorphism in TLR3 Confers Natural Resistance to HIV-1 Infection

“…Yet, studies in mice and humans have indicated that TLR3 may act as a double-edge sword during viral infection and subsequent pathology. In fact, Tlr3 2/2 mice display increased mortality after infection with murine CMV, encephalomyocarditis virus, coxsackievirus B, and intracranially inoculated West Nile virus (WNV) (17)(18)(19)(20). Conversely, animals lacking a functional Tlr3 gene display milder pathology when challenged with phlebovirus, influenza A virus, and i.p.-administered WNV (21-23).…”

The TLR3/TICAM-1 Pathway Is Mandatory for Innate Immune Responses to Poliovirus Infection

“…TLR3 2/2 or TICAM-1 2/2 mice became more resistant to WNV infection than did WT mice (52). Compared to these earlier results, a recent report showed that lack of TLR3 enhances WNV mortality and increases viral burden in the brain (53). TNF-a and IL-6 are induced for inflammation, and high IL-10 production causes an increase of mortality in WNV-infected mice (54).…”

“…TNF-a and IL-6 are induced for inflammation, and high IL-10 production causes an increase of mortality in WNV-infected mice (54). TICAM-1 signaling is undoubtedly involved in the modulation of these cytokine productions and WNV replication in the nervous system (53,54). In patients with herpes simplex encephalitis, functional deficiency of TLR3 or TICAM-1 is a critical factor for disease progression (55).…”

The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair

“…This study also linked TLR3 to a TNF-α-mediated reduction in blood-brain barrier (BBB) integrity upon WNV infection. However, a subsequent study reported that TLR3 deficiency resulted in enhanced WNV replication in primary cortical neurons, and that viral replication was actually increased in the brain and spinal chord of Tlr3 -/-mice [31]. The contrasting conclusions from these studies [30,31] may reflect differences in viral doses and/or routes of administration used.…”

“…Additionally, children with a particular TLR3 polymorphism (rs5743313/CT) have an increased risk of pneumonia caused by the pandemic IAV/H1N1 (2009) [29]. Complex roles for TLR3 in host protection versus immunopathology have also reported in other viral infection models, for example West Nile virus (WNV) [30,31]. An initial study showed that Tlr3 -/-mice were protected from WNV-induced encephalitis, because of reduced viral entry into the central nervous system [30].…”