Pattern recognition receptors and the innate immune response to viral infection

Abstract

The innate immune response to viral pathogens is critical in order to mobilize protective immunity. Cells of the innate immune system detect viral infection largely through germline-encoded pattern recognition receptors (PRRs) present either on the cell surface or within distinct intracellular compartments. These include the Toll-like receptors (TLRs), the retinoic acid-inducble gene I-like receptors (RLRs), the nucleotide oligomerization domain-like receptors (NLRs, also called NACHT, LRR and PYD domain proteins) and cytosolic DNA sensors. While in certain cases viral proteins are the trigger of these receptors, the predominant viral activators are nucleic acids. The presence of viral sensing PRRs in multiple cellular compartments allows innate cells to recognize and quickly respond to a broad range of viruses, which replicate in different cellular compartments. Here, we review the role of PRRs and associated signaling pathways in detecting viral pathogens in order to evoke production of interferons and cytokines. By highlighting recent progress in these areas, we hope to convey a greater understanding of how viruses activate PRR signaling and how this interaction shapes the anti-viral immune response.

Keywords: AIM2 like receptor; RIG-I like receptor; cytosolic DNA sensor; inflammasome; interferon; nod like receptor; pattern recognition receptor; toll like receptor; virus.

Figure 1.

Cell surface and endosomal recognition of viruses by Toll-like receptors (TLRs). TLR2 responds to a variety of viruses resulting in activation of a MyD88-dependent NF-κB and MAPK pathway. TLR4, responding to viral proteins (e.g., RSV F-protein) activates both a MyD88-dependent and MyD88-independent response. The MyD88-dependent response leads to transcriptional regulation of inflammatory cytokines, while the MyD88-independent response is regulated via TRAM/TRIF and the IKK-related kinases which drive IRF3 activation and type I Interferon production. In the endosome, TLR3, TLR7, TLR8 and TLR9 sense viral nucleic acids and generate either IRF3 activation (TLR3) or IRF7-driven type I IFNs (TLR7, 8 and 9).

Figure 2.

Cytosolic and Nuclear Pattern Recognition Receptors (PRRs). A multitude of DNA sensors, including IFI16, RNA Polymerase III, DAI, LRRFIP1, and DDX9/36 recognize DNA and drive type I IFNs and cytokine production. RIG-I and MDA5 recognize RNA in the cytosol. All of these molecules converge on STING in the case of DNA or MAVS in the case of RNA. STING and MAVS then engage either the TBK1-IRF3 or the IKKb-NFkB pathways, resulting in the activation of type I IFN responses and inflammatory cytokines, respectively. AIM2 (which binds to dsDNA) and NLRP3 (which can respond to viral RNA (probably indirectly)) act in the cytosol to promote the formation of a multiprotein inflammasome complex that contains the adaptor protein ASC, and caspase-1. IFI16 can also detect DNA in the nucleus during KSHV infection. Nuclear IFI16 engages ASC which then triggers caspase-1 in the cytosol. Activation of caspase-1 results in the proteolytic cleavage of pro-IL-1β and pro-IL-18 to IL-1β and IL-18, respectively. The mature cytokines can then be released from the cell.