A cytomegalovirus inflammasome inhibitor curbs proinflammatory cytokine release and pyroptosis

Abstract

In response to viral infection, cells can initiate programmed cell death (PCD), leading to a reduction in the release of viral progeny. Viruses have therefore evolved specific mechanisms to curb PCD. Cytomegaloviruses (CMVs) are particularly sophisticated manipulators of cellular defenses and are known to encode potent inhibitors of apoptosis and necroptosis. However, a CMV inhibitor of pyroptosis, the third major PCD form, has not been identified. Encoding such an inhibitor should be important for the virus as the three PCD pathways are not separate entities but interconnected pathways. Here we identify the murine CMV M84 protein as an inhibitor of pyroptosis and proinflammatory cytokine release. M84 interacts with the pyrin domain of the inflammasome components AIM2 and ASC to block Caspase-1 activation, release of interleukin 1β (IL-1β) and IL-18, cleavage of Gasdermin D, and pyroptosis of macrophages. Growth attenuation of an M84-deficient MCMV in macrophages was rescued by knockout of either Aim2 or Asc or by treatment with a Caspase-1 inhibitor, and its attenuation in infected mice was partially rescued in Asc knockout mice. These results demonstrate that viral inhibition of the inflammasome-pyroptosis pathway is important to promote viral replication and dissemination in vivo.