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Chapter 2 : Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses

Authors: Andrew G. Bowie1, Sinéad E. Keating2
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Affiliations: 1: School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland; 2: School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland
Content Type: Monograph
Publication Year: 2009

Category: Viruses and Viral Pathogenesis; Microbial Genetics and Molecular Biology

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Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses, Page 1 of 2

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Abstract:

Innate immunity is based on an intricate system of host pattern recognition receptors (PRRs) that specifically recognize pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) are ubiquitously and constitutively expressed on many different cell types including both immune and nonimmune cells. Cytotoxic T lymphocytes (CTLs) are potentially the most important protective component of host immunity to an array of viruses. Thus, the significance of TLRs in preventing virus-induced disease may lie in this cross talk between the innate immune response and antigen-specific adaptive immunity. The RNA viruses described in this chapter are all from distinct virus families, highlighting the overall importance of TLR2 and TLR4 in sensing RNA viral proteins as immediate danger signals of virus infection. RNA viruses have evolved specific mechanisms to inhibit TLR signaling pathways, and this provides compelling evidence for the importance of TLR-induced antiviral immunity in controlling RNA virus replication. In naturally occurring virus infections, TLR3 may in fact play a key role in controlling virus spread through the induction of a less damaging proinflammatory response to much lower viral doses. The exact physiological role of TLR3 in host innate immunity to RNA viruses has remained somewhat elusive. Cell-type specificity is a critical consideration in assessing the physiological contribution of TLRs to the innate immune response to RNA viruses. Priming an efficient immune response would potentially allow the host to limit replication of the virus and hence limit disease progression and even potentially lead to viral clearance.

Citation: Bowie A, Keating S. 2009. Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses, p 9-27. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch2
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Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses
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Citation: Bowie A, Keating S. 2009. Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses, p 9-27. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch2
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Figure 1
Activation of NF-κB by TLRs. Upon engagement of viral PAMPs at the surface of the cell (for TLR2 and TLR4) or within endosomal compartments (for TLR3 and TLR7/8), TLR dimerization occurs. This induces conformational changes within the receptor TIR domains, allowing them to recruit the appropriate downstream TIR adaptor via TIR:TIR domain associations. This is followed by activation of the IRAKs and, critically, triggering of TRAF6 ubiquitination by IRAK-2. Lysine-63-linked polyubiquitin chains conjugated to TRAF6 are specifically recognized by TAB2/3, which results in activation of the TAK1 complex and subsequent phosphorylation of the IKK complex by TAK1. TAK1-mediated phosphorylation of MKK6 leads to JNK and p38 MAP kinase activation. Phosphorylation of IκB-α by the activated IKK complex is coupled to lysine-48-linked ubiquitination of IκB-α and its subsequent proteasomal degradation. This allows NF-κB dimers to translocate into the nucleus and induce transcription of proinflammatory cytokines.
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Figure 1

Activation of NF-κB by TLRs. Upon engagement of viral PAMPs at the surface of the cell (for TLR2 and TLR4) or within endosomal compartments (for TLR3 and TLR7/8), TLR dimerization occurs. This induces conformational changes within the receptor TIR domains, allowing them to recruit the appropriate downstream TIR adaptor via TIR:TIR domain associations. This is followed by activation of the IRAKs and, critically, triggering of TRAF6 ubiquitination by IRAK-2. Lysine-63-linked polyubiquitin chains conjugated to TRAF6 are specifically recognized by TAB2/3, which results in activation of the TAK1 complex and subsequent phosphorylation of the IKK complex by TAK1. TAK1-mediated phosphorylation of MKK6 leads to JNK and p38 MAP kinase activation. Phosphorylation of IκB-α by the activated IKK complex is coupled to lysine-48-linked ubiquitination of IκB-α and its subsequent proteasomal degradation. This allows NF-κB dimers to translocate into the nucleus and induce transcription of proinflammatory cytokines.

Citation: Bowie A, Keating S. 2009. Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses, p 9-27. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch2
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Figure 2
Activation of IRFs by TLRs. Upon binding of their associated viral PAMPs, TLR3 and TLR4 trigger activation of IRF3 and IRF7 via the TIR adaptor TRIF. TLR3 recruits TRIF directly while TLR4 engages TRIF through the bridging adaptor TRAM. TRIF stimulates activation of the noncanonical IKK kinases, TBK1 and IKK-ε, through associations with TRAF3 and NAP1. These kinases mediate phosphorylation of IRF3 and IRF7, facilitating their dimerization and translocation to the nucleus, where they upregulate the transcription of type I interferons (IFN-α and IFN-β). TLR7/8 recruits the TIR adaptor MyD88, which then activates the serine/threonine kinases IRAK-4 and IRAK-1. IRAK-1 can then go on to directly phosphorylate IRF7 in a process that requires TRAF6 and TRAF3. Opsonin and IKK-α have also been implicated in this signaling process, but the exact details of their involvement have yet to be deciphered.
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Figure 2

Activation of IRFs by TLRs. Upon binding of their associated viral PAMPs, TLR3 and TLR4 trigger activation of IRF3 and IRF7 via the TIR adaptor TRIF. TLR3 recruits TRIF directly while TLR4 engages TRIF through the bridging adaptor TRAM. TRIF stimulates activation of the noncanonical IKK kinases, TBK1 and IKK-ε, through associations with TRAF3 and NAP1. These kinases mediate phosphorylation of IRF3 and IRF7, facilitating their dimerization and translocation to the nucleus, where they upregulate the transcription of type I interferons (IFN-α and IFN-β). TLR7/8 recruits the TIR adaptor MyD88, which then activates the serine/threonine kinases IRAK-4 and IRAK-1. IRAK-1 can then go on to directly phosphorylate IRF7 in a process that requires TRAF6 and TRAF3. Opsonin and IKK-α have also been implicated in this signaling process, but the exact details of their involvement have yet to be deciphered.

Citation: Bowie A, Keating S. 2009. Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses, p 9-27. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch2
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Tables

Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses
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Citation: Bowie A, Keating S. 2009. Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses, p 9-27. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch2
/content/10.1128/9781555815561.ch02.ch02tab01
Table 1
PAMPs presented by RNA viruses and the TLRs that specifically detect them
Generic image for table
Table 1

PAMPs presented by RNA viruses and the TLRs that specifically detect them

Citation: Bowie A, Keating S. 2009. Role of Toll-Like Receptors in the Innate Immune Response to RNA Viruses, p 9-27. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch2

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