The inflammasome as a target of modulation by DNA viruses.

Abstract

The cellular innate immune response represents the initial reaction of a host against infecting pathogens. Host cells detect incoming microbes by way of a large and expanding array of receptors that react with evolutionarily conserved molecular patterns exhibited by microbial intruders. These receptors are responsible for initiating signaling that leads to both transcriptional activation of immunologically important genes as well as protease-dependent processing of cellular proteins. The inflammasome refers to a protein complex that functions as an activation platform for the cysteine protease caspase-1, which then processes inflammatory molecules such as IL-1β and IL-18 into functional forms. Assembly of this complex is triggered following receptor-mediated detection of pathogen-associated molecules. Receptors have been identified that are essential to inflammasome activation in response to numerous molecular patterns including virus-associated molecules such as DNA. In fact, the importance of cytoplasmic DNA as an immune stimulus is exemplified by the existence of at least nine distinct cellular receptors capable of initiating innate reactivity in response to this molecule. Viruses that employ DNA as genomic material include herpesviruses, poxviruses and adenoviruses. Each has been described as capable of inducing inflammasome-mediated activity. Interestingly, however, the cellular molecules responsible for these responses appear to vary according to host species, cell type and even viral strain. Secretion of IL-1β and IL-18 are important components of antimicrobial immunity and, as a result, pathogens have evolved factors to evade or counteract this response. This includes DNA-based viruses, many of which encode multiple redundant counteractive molecules. However, it is clear that such phenotypes are only beginning to be uncovered. The purpose of this review is to describe what is known regarding the activation of inflammasome-mediated processes in response to infection with well-examined families of DNA viruses and to discuss characterized mechanisms of manipulation and neutralization of inflammasome-dependent activity. This review aims to shed light on the biologically important phenomena regarding this virus-host interaction and to highlight key areas where important information is lacking.