Chapter 15 : Innate Immunity to Viruses

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Viruses are the most abundant infectious agents on earth and the most primitive form of life, predating us by billions of years. Due to the fact that viruses utilize host cell machinery to replicate, the host has the daunting task of distinguishing virus infection signatures from self-molecules. This chapter provides an overview of the mechanisms used to sense virus infection (innate recognition), the cytokine system that evolved to rapidly induce antiviral states in neighboring cells (type I interferons), and the methods used to contain and destroy viruses (effector functions). Analysis of animals deficient in the RIG-I-like receptors (RLRs) revealed important and distinct roles for the sensing molecules in innate immunity. DNA viruses such as adenovirus stimulate the NLRP3-ASC-caspase-1 inflammasomes in vivo. The existence of a TLR-independent cytoplasmic DNA sensing molecule leading to type I IFN production was suggested from studies utilizing DNA viruses and bacteria. The mechanism of RNAi involves two steps. First, viral dsRNA is recognized by Dicer-like endonuclease family, which processes it into siRNA. Second, the siRNA are incorporated into RNA-induced silencing complex (RISC), which guide the RNase enzyme AGO to complementary sequences (viral RNA) for cleavage and degradation of viral RNA. Tetherin associates with lipid rafts and inhibits retrovirus particle release in the absence of Vpu. Vpu utilizes the beta-TrCP E3 ubiquitin ligase complex to induce endosomal trafficking events that remove tetherin from the cell surface, rendering it incapable of restricting the release of enveloped viruses.

Citation: Iwasaki A. 2011. Innate Immunity to Viruses, p 185-196. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch15
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Image of FIGURE 1

Intracellular trafficking and processing of endosomal TLRs. TLR3/7/9 require an ER-chaperone UNC93B for transport to the Golgi and the endolysosome. Pro-form TLR9 (full-length) is cleaved by cathepsins in the endolysosome, which is required for MyD88 recruitment and signaling. Endosomal TLRs recognize viral nucleic acids and dimerize to induce signaling, leading to the transcription of proinflammatory cytokines (via NF-κB) and type I IFNs (via IRFs).

Citation: Iwasaki A. 2011. Innate Immunity to Viruses, p 185-196. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch15
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Image of FIGURE 2

Signaling cascade of endosomal TLRs. Upon recognition of dsRNA, TLR3 utilizes TRIF to induce activation of NF-κB, MAPK, and IRF3 pathways. In contrast, TLR7 and 9 recognize viral RNA and DNA and engage MyD88 to induce NF-κB/IRF5, MAPK, and IRF7 activation. These transcription factors enter the nucleus, bind to conserved sequences in the promoter regions, and induce expression of a variety of genes required for innate and adaptive antiviral defense.

Citation: Iwasaki A. 2011. Innate Immunity to Viruses, p 185-196. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch15
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Viral recognition and signaling via RLRs. RIG-I recognizes 5′ triphosphate RNA and/or short dsRNA (or a panhandle RNA structure which contains both) whereas MDA5 recognizes long dsRNA. RNA binding to the helicase region enables exposure of the CARD domains of RLRs, which bind to the CARD domain of MAVS located on the outer mitochondrial membrane. MAVS recruits TRAF3 and activates IRF3 and NF-κB pathways. LGP2 also binds to dsRNA but lacks the CARD domain necessary for signaling.

Citation: Iwasaki A. 2011. Innate Immunity to Viruses, p 185-196. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch15
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Image of FIGURE 4

Viral recognition and activation of inflammasomes by NLRs. Caspase-1 is present as a pro-form in noninfected cells. Upon viral infection, TLR signaling provides signal 1, which induces transcription of proforms of IL-1b, IL-18, and IL-33. In addition, virally infected cells, signal 2 activates NLRP3 to form the inflammasome complex consisting of NLRP3/ASC/caspase-1, whereby pro-caspase-1 is cleaved to form active caspase-1. Another pathway leading to the activation of caspase-1 is via recognition of viral cytosolic dsDNA by AIM2, which forms a inflammasome complex consisting of AIM2/ASC and caspase-1. Release of mature forms of IL-1b, IL-18, and IL-33 requires processing by active caspase-1.

Citation: Iwasaki A. 2011. Innate Immunity to Viruses, p 185-196. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch15
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Ancient antiviral effector mechanisms. (A) In plants and invertebrates, the RNAi pathway plays a major role in the recognition and destruction of viral RNA. Viral dsRNA is recognized by Dicer, which process such RNA into short RNAi (~20 bp). The processed RNAi is incorporated into the RISC complex, which serves as the guide strand. The guide strand base pairs with a complementary sequence of a viral RNA molecule and induces its cleavage by AGO, the catalytic component of the RISC complex. (B) From insects to humans, xenophagy is used to limit viral replication in the cytosol. A double membrane structure called phagophore forms around the invading or replicating virus, engulfing it into autophagosome. Encapsulated virions are degraded when autophagosomes fuse with lysosomes.

Citation: Iwasaki A. 2011. Innate Immunity to Viruses, p 185-196. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch15
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Image of FIGURE 6

IFN-αβR signaling. Upon binding of type I IFNs, IFN-αR1, and IFN-αR2 dimerize to form an active type I IFN receptor. This induces phosphorylation of JAK1 and TYK2, resulting in phosphorylation of STAT1 and STAT2. STAT1 can form homodimers with another STAT-1 or can form a trimolecular complex between STAT2 and IRF9 (called ISGF3) and can translocate to the nucleus to induce transcription of ISGs via binding to conserved DNA sequences (GAS and ISRE).

Citation: Iwasaki A. 2011. Innate Immunity to Viruses, p 185-196. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch15
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