Cytosolic surveillance and antiviral immunity

Abstract

Innate immune surveillance mechanisms lie at the heart of the antiviral response. A growing number of germ-line encoded pattern recognition receptors have been identified which protect the host from infection by sensing the presence of viral molecules and inducing antiviral defenses. Most compartments that viruses gain access to are under active surveillance by one or more pattern recognition receptors. Members of the Toll-like receptor family guard the extracellular milieu and endosomal compartment where they are activated by viral glycoproteins or nucleic acids, respectively. More recently, the cytosolic compartment has emerged as the frontline in the arsenal of the host's antiviral defenses. Families of receptors in the cytosol recognize viral RNA or DNA or perturbations of cellular homeostasis and orchestrate effector responses to eliminate the invader. Here, we review this expanding area of innate immunity by focusing on the molecular mechanisms of cytosolic host-defenses.

Figure 1

Cytosolic receptors that sense viruses and induce type I interferons. Most cytosolic receptors that recognize RNAs such as RIG-I, MDA5, NOD2 activate TBK1–IRF3 via the mitochondria-associated MAVS. A recently identified receptor complex consisting of DDX1, DDX21, and DHX36 signals via TRIF to activate TBK1 after sensing RNA. On the other hand, DNA sensing in the cytosol triggers signaling via STING–TBK1–IRF3 axis to induce type I interferon production. RNA polymerase III recognizes cytosolic DNA and generates stimulatory RNA, which is subsequently detected by RIG-I. DHX9 and DDX36 sense cytosolic CpG and activate IRF7 via MyD88.

Figure 2

Cytosolic receptors that sense viruses and induce inflammasome activation. NLRP3, AIM2, IFI16 sense viral infections and recruit ASC to form caspase-1-containing inflammasome complexes. The autoproteolytic processing of procaspase-1 results in the generation of active caspase-1, which then processes proIL-1β and proIL-18 to IL-1β and IL-18, respectively. The active caspase-1 also mediates an inflammatory form of cell death called pyroptosis.