Transcending cell death - The diverse roles of necroptosis signal adaptors in pathogen infection

Necroptosis is a critical host response against pathogenic challenge. As such, many pathogens have developed strategies to fend off host cell necroptosis. This tug-of-war between the host and pathogen has led to the widely held view that necroptosis evolves primarily as a host response to infection. Paradoxically, pathogens that encode caspase inhibitors and therefore render infected cells sensitive to necroptosis also develop strategies that block necroptosis. Hence, cell death alone may not be sufficient to account for the protective role of necroptosis signal adaptors in host defense. We propose an alternative model in which cell death signal adaptors function as sensors of pathogen-encoded activities. In this scenario, pathogen interference with necroptosis may not only affect host cell death but also tune the magnitude and quality of the ensuing immune response. The crosstalk between necroptosis and other inflammatory cell death programs during viral infection will also be discussed.