A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection.
Proinflammatory caspases play an essential role in innate immune responses to infection by regulating the cleavage and activation of proinflammatory cytokines. Activation of these enzymes requires the assembly of an intracellular molecular platform, termed the inflammasome, which is comprised of members of the pyrin domain (PYD)-containing superfamily of apoptosis and inflammation-regulatory proteins. We report here the identification and characterization of a poxvirus-encoded PYD-containing protein that interacts with the ASC-1 component of the inflammasome and inhibits caspase-1 activation and the processing of IL-1beta and IL-18 induced by diverse stimuli. Knockout viruses that do not express this protein are unable to productively infect monocytes and lymphocytes due to an abortive phenotype and are markedly attenuated in susceptible hosts due to decreased virus dissemination and enhanced inflammatory responses at sites of infection. Thus, modulation of inflammasome function constitutes an important immunomodulatory strategy employed by poxviruses to circumvent host antiviral responses.
Johnston
James B
JB
BioTherapeutics Research Group, Robarts Research Institute, 1400 Western Road, London, Ontario N6G 2V4, Canada.
Barrett
John W
JW
Nazarian
Steven H
SH
Goodwin
Megan
M
Ricciuto
Dan
D
Ricuttio
Dan
D
Wang
Gen
G
McFadden
Grant
G
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism*; D019295:Computational Biology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology* / Q000821:virology; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D018448:Models, Immunological; D008969:Molecular Sequence Data; D009233:Myxoma virus / Q000235:genetics / Q000276:immunology*; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D007375:Interleukin-1; D020382:Interleukin-18; C402202:PYCARD protein, human; D014764:Viral Proteins; D020170:Caspase 1