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Review
. 2013 Jan 31;5(2):470-527.
doi: 10.3390/v5020470.

Learning from the messengers: innate sensing of viruses and cytokine regulation of immunity - clues for treatments and vaccines

Jesper Melchjorsen  1
Affiliations
Review

Learning from the messengers: innate sensing of viruses and cytokine regulation of immunity - clues for treatments and vaccines

Jesper Melchjorsen. Viruses. .

Abstract

Virus infections are a major global public health concern, and only via substantial knowledge of virus pathogenesis and antiviral immune responses can we develop and improve medical treatments, and preventive and therapeutic vaccines. Innate immunity and the shaping of efficient early immune responses are essential for control of viral infections. In order to trigger an efficient antiviral defense, the host senses the invading microbe via pattern recognition receptors (PRRs), recognizing distinct conserved pathogen-associated molecular patterns (PAMPs). The innate sensing of the invading virus results in intracellular signal transduction and subsequent production of interferons (IFNs) and proinflammatory cytokines. Cytokines, including IFNs and chemokines, are vital molecules of antiviral defense regulating cell activation, differentiation of cells, and, not least, exerting direct antiviral effects. Cytokines shape and modulate the immune response and IFNs are principle antiviral mediators initiating antiviral response through induction of antiviral proteins. In the present review, I describe and discuss the current knowledge on early virus-host interactions, focusing on early recognition of virus infection and the resulting expression of type I and type III IFNs, proinflammatory cytokines, and intracellular antiviral mediators. In addition, the review elucidates how targeted stimulation of innate sensors, such as toll-like receptors (TLRs) and intracellular RNA and DNA sensors, may be used therapeutically. Moreover, I present and discuss data showing how current antimicrobial therapies, including antibiotics and antiviral medication, may interfere with, or improve, immune response.

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Figures

Figure 1
Figure 1
Viral PAMPs and cell PRRs. The viral particle constitutes of a viral genome of either RNA or DNA sensed by both membrane-associated receptors and receptors in the cytoplasm. DNA sensors include TLR9, AIM2, IFI16, DDX4, DHX9, DHX36, Ku70, and RNA pol III. RNA sensors include TLR3, TLR7/8, MDA5, RIG-I, NLRP3, NOD2, LRRFIP1, PKR, and IFIT1. The genome is surrounded by a capsid, which in the case of HIV is sensed by cyclophilin A (CYPA) and TRIM5. The outer surface of a major number of viruses consists of a lipid membrane with embedded glycoproteins. Virus surface structures are sensed by the cells via TLR2 and TLR4.
Figure 2
Figure 2
Viral sensors localized at membranes and in cytoplasm and nucleus. TLR2 and TLR4 located at the surface of the cell senses surface structures from a number of viruses, including HSV, CMV, VV, MV, RSV, and HCV. After internalization viral DNA genomes, typically from herpes viruses and VV, may be recognized by the DNA sensors IFI16, DAI, Ku70, AIM2, DDX41, RNA pol III, DHX9 or DHX36 localized in the cytoplasm or for IFI16 possibly also in the nucleus. Genomic DNA may also be recognized by TLR9 localized in endosomes. Viral genomic RNA or RNA structures’ accumulation during infection is recognized by the RLRs RIG-I or MDA5, the NLRs NOD2 or NLRP3 or the protein LRRFIP1. In addition, dsRNAs and ssRNAs localized in the endosomal compartments are recognized via TLR3 and TLR7/8, respectively. Signaling from TLRs proceed via the adaptor protein MyD88 (TLR2, TLR4, TLR7/8, and TLR9) and TRIF (TLR3 and TLR4). Signaling from DNA receptors is mediated via STING for at least the DNA receptors DAI, IFI16, and DDX41. Signaling from RIG-I and MDA5 proceeds via the signaling protein MAVS.
Figure 3
Figure 3
PRR activated signaling and antiviral responses during virus infection. An overview of signaling pathways triggering IFN and cytokine production and mediates an endogenous antiviral states after sensing of invading virus. TLR2, TLR4, TLR7/8, and TLR9 all signals via the adaptor molecule Myd88 and via TRAF6 and/or TRAF3 and IRAKs. TLR2 primarily mediates activation of NF-κB, whereas TLR3 and TLR4 also mediate activation of IRF3 via the adaptor molecule TRIF. TLR3 and TLR4 stimulation induce IFNβ production. TLR7/8 and TLR9 primarily activate IRF7 leading to immediate IFN-α expression, but also NF-κB activation leading to stimulation of proinflammatory cytokines. RNA sensors and DNA sensors lead to activation if both IRF3 and NF-κB thus regulating both IFN and cytokine production. DNA sensors IFI16, DAI, and DDX41 signals via STING located at the ER whereas the RNA sensors RIG-I and MDA5 signal via MAVS. Finally, the DNA sensors AIM2 and IIF16 and the RNA sensor NLRP3 participate in inflammasome formation and cleavage of pro-IL-1β to IL-1β. Secreted IFN binds to its receptor and activates JAK/STAT signaling pathways leading to enhanced IFN expression and induction of antiviral mediators, including OASs, PKR, IFIT1, APOBEC3, and viperin, as well as production of IRF7 inducing IFN-α responses and thus increase overall IFN secretion. The MAPK signaling pathway activated by several PRRs, including TLRs and RLRs, has been omitted in the figure. ER = endoplasmic reticulum.
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