Staying alive: cell death in antiviral immunity

Abstract

Programmed cell death is an integral part of host defense against invading intracellular pathogens. Apoptosis, programmed necrosis, and pyroptosis each serve to limit pathogen replication in infected cells, while simultaneously promoting the inflammatory and innate responses that shape effective long-term host immunity. The importance of carefully regulated cell death is evident in the spectrum of inflammatory and autoimmune disorders caused by defects in these pathways. Moreover, many viruses encode inhibitors of programmed cell death to subvert these host responses during infection, thereby facilitating their own replication and persistence. Thus, as both virus and cell vie for control of these pathways, the battle for survival has shaped a complex host-pathogen interaction. This review will discuss the multifaceted role that programmed cell death plays in maintaining the immune system and its critical function in host defense, with a special emphasis on viral infections.

Figure 1

The major cell death pathways at a glance. The extrinsic (death receptors) and intrinsic (mitochondria) apoptosis pathways intersect at the mitochondria and cumulate in the formation and activation of the apoptosome. In some cell types, death receptors can bypass the mitochondria to directly engage downstream effector caspases. When caspase 8 is inactivated, RIP1 forms an amyloid-like signaling complex with RIP3 to recruit downstream effectors such as MLKL and PGAM5. ROS may act upstream to strengthen necrosis signaling, or downstream to induce cellular damages such as membrane rupture for the execution of necrosis. Pyroptosis, which is triggered by the inflammasome, is also marked by rapid membrane rupture. Whereas apoptotic cells are rapidly engulfed and cleared by phagocytes such as macrophages, necrosis and pyroptosis promote inflammation through leakage of cellular “danger signals”.

Figure 2

Interaction of viral inhibitors with host cell death machineries. (A) Ligation of death receptors (DRs) induces recruitment and association of FADD, RIP1 and caspase 8. The activity of caspase 8 negatively regulates necrotic signaling by cleavage of RIP1 and RIP3 as well as initiates the proteolytic cascade of apoptosis. (B) Infection of cells with vaccinia virus (VV) leads to expression and release of DR cytokines. VV encodes the B13R gene product, which potently inhibits caspase 8. Signaling via the DR proceeds in the absence of caspase 8 activity results in necrosome formation and anti-viral necrosis. (C) Murine cytomegalovirus (MCMV) encodes inhibitors of apoptosis and necrosis to promote survival and viral replication. MCMV expresses the viral Inhibitor of Caspase Activity (vICA), which binds and inhibits capsase 8. This normally sensitizes cells to necrosis through DAI, a RIP3 interacting partner. However, MCMV also expresses the viral Inhibitor of RIP Activation (vIRA) that directly targets RIP3 to prevent association with DAI and initiation of necrotic signaling. (D) Functional inactivation of the vIRA RHIM releases RIP3 from inhibition, resulting in antiviral necrosis. (E) Some poxvirus- and herpesviruses-encoded vFLIPs (e.g. MC159, K13, E8) are strong inhibitors of apoptosis and necrosis. Although the underlying mechanism remains unclear, the net result is dual-functioning cell death inhibitors capable of preventing both apoptosis and necrosis to promote cell survival and viral persistence.