Recognition of viruses by cytoplasmic sensors

Abstract

The immune response to virus infection is initiated when pathogen recognition receptors (PRRs) of the host cell recognize specific nonself-motifs within viral products (known as a pathogen-associated molecular pattern or PAMP) to trigger intracellular signaling events that induce innate immunity, the front line of defense against microbial infection. The replication program of all viruses includes a cytosolic phase of genome amplification and/or mRNA metabolism and viral protein expression. Cytosolic recognition of viral infection by specific PRRs takes advantage of the dependence of viruses on the cytosolic component of their replication programs. Such PRR-PAMP interactions lead to PRR-dependent nonself-recognition and the downstream induction of type I interferons and proinflammatory cytokines. These factors serve to induce innate immune programs and drive the maturation of adaptive immunity and inflammation for the control of infection. Recent studies have focused on identifying the particular viral ligands recognized as nonself by cytosolic PRRs, and on defining the nature of the PRRs and their signaling pathways involved in immunity. The RIG-I-like receptors, RIG-I and MDA5, have been defined as essential PRRs for host detection of a variety of RNA viruses. Novel PRRs and their signaling pathways involved in detecting DNA viruses through nonself-recognition of viral DNA are also being elucidated. Moreover, studies to identify the PRRs and signaling factors of the host cell that mediate inflammatory signaling through inflammasome activation following virus infection are currently underway and have already revealed specific NOD-like receptors (NLRs) as inflammatory triggers. This review summarizes recent progress and current areas of focus in pathogen recognition and immune triggering by cytosolic PRRs.

Figure 1

Upper: RLR structure diagram showing positions of functional domains. Lower: 3-step model of RIG-I activation from a monomeric resting form (left) to RNA-ligand bound, dimeric form (center) and the final active form (right). The positions of the CARDs, helicase domain, and repressor domain (RD) are indicated. Ligand binding by RIG-I facilitates a conformation change that releases it from autorepression by the RD, thus driving downstream signaling of innate antiviral immunity. Model adapted from reference .

Figure 2

The RLR signaling pathway showing RIG-I bound to ligand RNA and signaling downstream to IRF-3 and NF-kB to induce IFN-α/β production from a virus-infected cell. IFN-α/β is then shown signaling through the IFN-α/β receptor and the Jak-STAT pathway to drive ISG expression and an innate immune response. Details are described in the text.

Figure 3

PRR signaling of the inflammasome. Model shows signaling by NLRP3 during influenza virus infection. Host metabolite products and/or viral products such as nucleic acid or viral protein serve as specific NLR ligands to trigger NLRP3 signaling activation. Adapted from reference .