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

Abstract

SummaryViral 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 domaincontaining adaptor protein interferon-b (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.

Dectin-1 Is Expressed in Human Lung and Mediates the Proinflammatory Immune Response to Nontypeable Haemophilus influenzae

“…Thus, Dectin-1 expression seems to be differently regulated in different cell types. An activation of innate immune response by TLR3 via detection of viral double-stranded RNA (dsRNA) is described for a wide range of respiratory viral infections, such as the respiratory viruses influenza A virus, respiratory syncytial virus, and rhinovirus type 1b (36). Therefore, it is possible that an upregulation of Dectin-1 expression in the airways is associated with the occurrence of viral infections, and it is tempting to speculate that this upregulation then influences the immune response to a secondary NTHI infection.…”

DDX19A Senses Viral RNA and Mediates NLRP3-Dependent Inflammasome Activation

“…At present, five main classes of PRRs have been identified: TLRs, retinoic acid inducible gene-I (RIG-I)-like receptors, nucleotidebinding domain/leucine-rich repeat (LRR)-containing receptors (NLRs), C-type lectin receptors, and PYRIN-HIN domain containing family member (including absent in melanoma 2) (3). It has been described that DEAD/H-box helicase family members (e.g., RIG-I, MDA5, DHX36, and DHX33) (4-6), TLRs (e.g., TLR2, TLR3, TLR4, and TLR7) (7)(8)(9)(10), and NLRs (e.g., NLRX1, NLRP1, and NLPR3) (11)(12)(13) are involved in type I IFN production or inflammatory responses.…”

IRAK4 as a Molecular Target in the Amelioration of Innate Immunity–Related Endotoxic Shock and Acute Liver Injury by Chlorogenic Acid

“…The transcription factors NF-kB and AP-1 upregulate gene expression of inflammatory cytokines and enzymes including TNF-a, IL-1a, IL-6, high-mobility group box-1 (HMGB-1), and inducible NO synthase (iNOS) (9,10). In contrast, TRIF-mediated innate immunity activates another transcription factor IFN regulatory factor 3 (IRF3) via TNFR-associated factor family member-associated NF-kB activator-binding kinase 1 (TBK1), thus triggering gene expression of IFN-g-induced protein 10 (IP-10) or IFN-b (11,12).…”