Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses

Abstract

Five of the 10 human Toll-like receptors (TLRs) (TLR3, TLR4, TLR7, TLR8, and TLR9), and four of the 12 mouse TLRs (TLR3, TLR4, TLR7, TLR9) can trigger interferon (IFN)-alpha, IFN-beta, and IFN-lambda, which are critical for antiviral immunity. Moreover, TLR3, TLR7, TLR8, and TLR9 differ from TLR4 in two particularly important ways for antiviral immunity: they can be activated by nucleic acid agonists mimicking compounds produced during the viral cycle, and they are typically present within the cell, along the endocytic pathway, where they sense viral products in the intraluminal space. Investigations in mice have demonstrated that the TLR7/9-IFN and TLR3-IFN pathways are different and critical for protective immunity to various experimental viral infections. Investigations in humans with interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency (unresponsive to TLR7, TLR8, and TLR9), UNC-93B deficiency (unresponsive to TLR3, TLR7, TLR8, and TLR9), and TLR3 deficiency have recently shed light on the role of these two pathways in antiviral immunity in natural conditions. UNC-93B- and TLR3-deficient patients appear to be specifically prone to herpes simplex virus 1 (HSV-1) encephalitis, although clinical penetrance is incomplete, whereas IRAK-4-deficient patients appear to be normally resistant to most viruses, including HSV-1. These experiments of nature suggest that the TLR7-, TLR8-, and TLR9-dependent induction of IFN-alpha, IFN-beta, and IFN-lambda is largely redundant in human antiviral immunity, whereas the TLR3-dependent induction of IFN-alpha, IFN-beta, and IFN-lambda is critical for primary immunity to HSV-1 in the central nervous system in children but redundant for immunity to most other viral infections.

Figure 1

An overview of the signaling pathways triggered by the interferon (IFN)‐inducing Toll‐like receptors (TLRs) (TLR3, TLR4, TLR7, TLR8 and TLR9) and human primary immunodeficiencies involving TLR‐signaling pathways. Five TLRs (TLR3, TLR4, TLR7, TLR8, and TLR9) have been shown to induce the production of IFN‐α, IFN‐β, and IFN‐λ. TLR7, TLR8, and TLR9 trigger the ‘classical’ MyD88‐dependent TLR pathway, via the TIR‐containing cytosolic adapter MyD88. TLR3 triggers the ‘alternative’ MyD88‐independent, TIR domain‐containing adapter inducing IFN‐β (TRIF)‐dependent pathway via the TRIF. TLR4 triggers the MyD88‐dependent TLR pathway, via the TIRAP–MyD88 interaction, and triggers the MyD88‐independent pathway, via the TRIF‐related adapter molecule(TRAM)–TRIF interaction. The MyD88‐dependent pathway results in the activation of both nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinases (MAPKs), via the interleukin‐1 receptor‐associated kinase (IRAK) complex, which comprises two active kinases (IRAK‐1 and IRAK‐4) and two non‐catalytic subunits (IRAK‐2 and IRAK‐M). The MyD88‐independent pathway results in the activation of IRF3 via two kinases: NF‐κB kinase ɛ (IKK‐ɛ) and TANK‐binding kinase‐1 (TBK‐1). TRAF family member‐associated NF‐κB activator (TANK) interacts with NF‐κB essential modulator (NEMO), TBK1, and IRF3 and may therefore liaise between the MyD88‐dependent and MyD88‐independent pathways. These signaling pathways triggered by TLRs have been dissected in mice and, to a lesser extent, in humans. The three proteins in the TLR signaling pathways (IRAK‐4, UNC‐93B, and TLR3) responsible for the human primary immunodeficiencies discussed in this review are shown in red, the other two proteins in the TLR signaling pathways (NEMO, IκBα) responsible for human primary immunodeficiencies not discussed here are shown in blue. The principal pathways proposed are indicated by solid arrows, and recently described important associations between molecules are indicated with dotted arrows.

Figure 2

Toll‐like receptors (TLR)3‐, TLR7‐, TLR8‐, and TLR9‐dependent induction of interferon (IFN)‐α, ‐β, and ‐λ is largely redundant in human antiviral immunity. Four of the five IFN‐inducing TLRs (TLR3, TLR7, TLR8, and TLR9) are intracellular in most cell types tested. Viral nucleic acids, including double stranded (ds) RNA, single stranded (ss) RNA, and DNA, produced during virus replication are thought to be detected by TLR3, TLR7/8, and TLR9, respectively, and to induce IFN production. The production of IFN‐α, ‐β, and ‐λ in response to TLR7, TLR8, and TLR9 stimulation is impaired in interleukin‐1 receptor‐associated kinase (IRAK)‐4‐deficient patients, who appear to be resistant to most viruses. The induction of IFN‐α, ‐β, and ‐λ by TLR3, TLR7, TLR8, and TLR9 is impaired in UNC‐93B‐deficient patients, who are prone to herpes simplex virus 1 encephalitis (HSE) but appear to be resistant to most viruses. The UNC‐93B–TLR3–IFN‐α, ‐β, and ‐λ pathway is presumably essential for primary immunity to HSV‐1 in the central nervous system (CNS) in children but is redundant for immunity to most other viral infections. The three proteins in the TLR signaling pathways (IRAK‐4, UNC‐93B, and TLR3) responsible for the human primary immunodeficiencies discussed in this review are shown in red; the other two proteins in the TLR signaling pathways (NEMO, IκBα) responsible for human primary immunodeficiencies not discussed here are shown in blue.