Necroptosis in anti-viral inflammation

Abstract

The primary function of the immune system is to protect the host from invading pathogens. In response, microbial pathogens have developed various strategies to evade detection and destruction by the immune system. This tug-of-war between the host and the pathogen is a powerful force that shapes organismal evolution. Regulated cell death (RCD) is a host response that limits the reservoir for intracellular pathogens such as viruses. Since pathogen-specific T cell and B cell responses typically take several days and is therefore slow-developing, RCD of infected cells during the first few days of the infection is critical for organismal survival. This innate immune response not only restricts viral replication, but also serves to promote anti-viral inflammation through cell death-associated release of damage-associated molecular patterns (DAMPs). In recent years, necroptosis has been recognized as an important response against many viruses. The central adaptor for necroptosis, RIPK3, also exerts anti-viral effects through cell death-independent activities such as promoting cytokine gene expression. Here, we will discuss recent advances on how viruses counteract this host defense mechanism and the effect of necroptosis on the anti-viral inflammatory reaction.

Fig. 1

Necroptosis in poxvirus infection. Control of vaccinia virus (VV) infection requires TNF signaling [9]. TNF signaling through its trimeric receptor (TNFR-1) triggers three distinct signaling responses: NF-κB activation, apoptosis or necroptosis. Vaccinia virus encodes the caspase inhibitor B13R/Spi2, which inhibits caspase 1 and caspase 8 and blocks apoptosis. Thus, in VV infection, TNF stimulation favors necroptosis. This leads to assembly of the RHIM–RHIM interaction between RIPK1–RIPK3 and necrosome formation. Certain viral FLIPs such as MC159 from Molluscum contagious virus (MCV) inhibit both apoptosis and necroptosis, although the mechanisms are not fully elucidated. The VV-encoded protein E3L contains a z-DNA binding domain that interacts with ZBP1 and senses viral RNA. E3L binding sequesters ZBP1 from RIPK3 and therefore prevents necroptosis. However, E3L does not interfere with TNF-induced necroptosis. VV Vaccinia virus, TRADD TNFRSF1A associated death domain, TRAF2 TNF receptor associated factor 2, cIAP cellular inhibitor of apoptosis, CYLD cylindromatosis, FADD Fas associated via death domain, IKK inhibitor of nuclear factor kappa B kinase, cFLIPL CASP8 and FADD like apoptosis regulator long isoform, MLKL mixed lineage kinase domain-like, RHIM RIP homotypic interaction motif, Zα1, Zα2 zDNA binding domain

Fig. 2

Necroptosis in herpesvirus and Influenza virus infection. Herpesviruses exploit the necroptotic pathway via various RHIM adaptors such as M45 from MCMV, ICP6 from HSV-1 and ICP10 from HSV-2. These viral inhibitors sequester ZBP1 and RIPK3 to prevent their interaction and activation. When viral RHIM inhibitors are absent, ZBP1 senses viral RNA (vRNA) to trigger RIPK3 binding and activation. The necroptosis modulating function of these viral RHIM adaptors varies with host species. For example, ICP6 and ICP10 prevent necroptosis in human cells, but stimulate RIPK3-dependent necroptosis in mouse cells. Though the molecular basis for the differential effects of ICP6 or ICP10 in different species is unknown, it may account for the species tropism of these viruses. In contrast to herpesvirus, IAV uses this mechanism to cause ZBP1/RIPK3-dependent necroptosis. MCMV murine cytomegalovirus, HSV herpes simplex virus, IAV Influenza A virus, vRNA viral RNA