Production upon Extrinsic Stimulation

Gammaherpesviruses establish lifelong infections that are associated with the development of cancer. These viruses subvert many aspects of the innate and adaptive immune response of the host. The inflammasome, a macromolecular protein complex that controls inflammatory responses to intracellular danger signals generated by pathogens, is both activated and subverted during human gammaherpesvirus infection in culture. The impact of the inflammasome response on gammaherpesvirus replica-tion and latency in vivo is not known. Caspase-1 is the inflammasome effector protease that cleaves the proinflammatory cyto-kines interleukin-1 (IL-1) and IL-18. We infected caspase-1-deficient mice with murine gammaherpesvirus 68 (MHV68) and observed no impact on acute replication in the lung or latency and reactivation from latency in the spleen. This led us to examine the effect of viral infection on inflammasome responses in bone marrow-derived macrophages. We determined that infection of macrophages withMHV68 led to a robust interferon response but failed to activate caspase-1 or induce the secretion of IL-1. In addition, MHV68 infection led to a reduction in IL-1 production after extrinsic lipopolysaccharide stimulation or upon coin-fection with Salmonella enterica serovar Typhimurium. Interestingly, this impairment occurred at the proIL-1 transcript level and was independent of the RTA, the viral lytic replication and transcription activator. Taken together, MHV68 impairs the in-flammasome response by inhibiting IL-1 production during the initial stages of infection. IMPORTANC