Toll-like receptor 3 in viral pathogenesis: friend or foe?

Abstract

Viral infections frequently induce acute and chronic inflammatory diseases, yet the contribution of the innate immune response to a detrimental host response remains poorly understood. In virus-infected cells, double-stranded RNA (dsRNA) is generated as an intermediate during viral replication. Cell necrosis (and the release of endogenous dsRNA) is a common event during both sterile and infectious inflammatory processes. The discovery of Toll-like receptor 3 (TLR3) as an interferon-inducing dsRNA sensor led to the assumption that TLR3 was the master sentinel against viral infections. This simplistic view has been challenged by the discovery of at least three members of the DExd/H-box helicase cytosolic sensors of dsRNA that share with TLR3 the Toll-interleukin-1 receptor (TIR) -adapter molecule TIR domain-containing adaptor protein interferon-β (TRIF) for downstream type I interferon signalling. Data are conflicting on the role of TLR3 in protective immunity against viruses in the mouse model. Varying susceptibility to infection and disease outcomes have been reported in TLR3-immunodeficient mice. Surprisingly, the susceptibility to develop herpes simplex virus-1 encephalitis in humans with inborn defects of the TLR3 pathway varies, and TLR3-deficient humans do not show increased susceptibility to other viral infections. Therefore, a current challenge is to understand the protective versus pathogenic contribution of TLR3 in viral infections. We review recent advances in the identification of TLR3-signalling pathways, endogenous and virus-induced negative regulators of the TLR3 cascade, and discuss the protective versus pathogenic role of TLR3 in viral pathogenesis.

Keywords: Toll-like receptor 3; negative regulation; pathogenesis; virus.

Figure 1

Role of Toll-like receptor 3 (TLR3) in the pathogenesis of viral infections in humans and mice shown by organ type. TLR3 may exhibit protective (+) or detrimental roles (−) in humans (a) and mice (b) depending on virus type. (a) A protective role of TLR3 in the central nervous system (CNS) has been suggested for herpes simplex virus type 1 (HSV-1) and influenza A virus (IAV) -induced encephalitis in humans. In contrast, TLR3 sensing of tick-borne encephalitis virus (TBEV) may contribute to neuropathogenesis in some infected individuals. Although the precise role of TLR3 in influenza infection in the lung remains unknown, children with a TLR3 polymorphism had an increased risk of pneumonia induced by the pandemic IAV/H1N1/2009 strain. Rotavirus is the leading cause of severe diarrhoea in infants and young children worldwide. Up-regulation of TLR3 expression during infancy might contribute to age-dependent susceptibility to rotavirus infection. HIV-1 induces AIDS and it can also cause several neurological disorders. Despite various studies demonstrating an antiviral role of the TLR3 pathway in cell culture, there is little evidence that TLR3 could play a major role in host defence in HIV-1-infected individuals. TLR3 expression is up-regulated in proximity to infiltrating mononuclear cells in biopsy specimens from patients with HIV-1 myopathies. The role of TLR3 in liver diseases induced by human hepatitis C (HCV) and B (HBV) viruses remains to be elucidated. Chronic over-stimulation of the TLR3 pathway may contribute to an unbalanced intrahepatic inflammatory response that is observed in chronic viral hepatitis. Some TLR3 polymorphisms have been associated with hepatocellular carcinoma in patients infected with HBV. (b) The role of TLR3 in the pathogenesis of various viral infections has been studied in TLR3-deficient mice. TLR3 plays a detrimental role in the pathogenesis of rhinovirus type 1B (RV1B), vaccinia virus (VACV), respiratory syncytial virus (RSV) and IAV in the lung. In contrast, TLR3 plays a protective role against the infection with herpes simplex virus type 2 (HSV-2) in the CNS. However, the contribution of TLR3 to West Nile virus (WNV) encephalitis remains controversial. In the liver, TLR3-deficient mice exhibit increased resistance to Punta Toro virus fatal infection, suggesting a detrimental role in phlebovirus pathogenesis. However, TLR3 mediates protection against poliovirus, coxsackievirus B (CVB3 and CVB4), and encephalomyocarditis virus (EMCV) infections in the liver, heart and pancreas of infected mice.

Figure 2

Toll-like receptor 3 (TLR3) participates in both defence and offence in host immunity to viruses. TLR3 recognizes dsRNA, a common intermediate of replication among many viruses. TLR3 dimerization and Tyr phosphorylation trigger the recruitment of the adaptor protein Toll–interleukin-1 receptor domain-containing adaptor protein interferon-β (TRIF), and induce the activation of the transcription factors interferon (IFN) regulatory transcription factor 3 (IRF3), nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) through two branches. TLR3 activation leads to (i) the development of an antiviral response mediated by IRF3 activation and further type I IFN production; (ii) cell death through a Fas-associated protein with death domain /caspase-8-dependent and mitochondrion-independent pathway (RIP1/ Fas-associated protein with death domain); and (iii) the generation of a pro-inflammatory environment by the activation of NF-κB and AP-1, and the mitogen-activated protein kinases (MAPK) the extracellular signal-regulated protein kinase 1/2 (ERK), the p38 MAP kinases (p38), and the c-Jun N-terminal kinase (JNK), which differentially regulate many cellular functions including inflammation-mediated inflammatory processes. Despite the detrimental role of TLR3 in viral pathogenesis being poorly understood, three major mechanisms have been identified: (i) over-expression of TLR3 (only observed in some viral infections but not others); (ii) over-production of cytokines [tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-12p40/p70, and IFN-γ], chemokines [regulated on activation, normal T-celll expressed and secreted (RANTES), IL-8, and monocyte chemoattractant protein-1 (MCP-1)], and the immune suppressive molecule programmed death ligand-1 (PDL-1); (iii) dysregulation of T helper type 1 and 2 (Th1/Th2) polarization. However, the precise molecular mechanisms that lead to TLR3 hyper-responsiveness are unknown. Over-production of inflammatory mediators leads to dysregulation of leucocyte trafficking, blood–brain barrier (BBB) permeability, and mechanisms to be identified. A detrimental role of TLR3 has been identified in mice infected with West Nile virus (WNV) and Theiler's murine encephalomyelitis (TMEV) (encephalitis), Punta Toro virus (PTV) (hepatitis), and in respiratory infections caused by respiratory syncytial virus (RSV), vaccinia virus, influenza A virus and rhinovirus RV1B (pneumonia). In humans, TLR3 may contribute to glomerulonephritis in patients with chronic hepatitis C virus infection. Finally, TLR3 hyper-responsiveness may play a detrimental role in virus-triggered autoimmunity.