Complementary regulation of caspase-1 and IL-1β reveals additional mechanisms of dampened inflammation in bats
Bats have emerged as unique mammalian vectors harboring a diverse range of highly lethal zoonotic viruses with minimal clinical disease. Despite having sustained complete genomic loss of AIM2, regulation of the downstream inflammasome response in bats is unknown. AIM2 sensing of cytoplasmic DNA trig...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 46; pp. 28939 - 28949 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
17.11.2020
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Subjects | |
Online Access | Get full text |
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Summary: | Bats have emerged as unique mammalian vectors harboring a diverse range of highly lethal zoonotic viruses with minimal clinical disease. Despite having sustained complete genomic loss of AIM2, regulation of the downstream inflammasome response in bats is unknown. AIM2 sensing of cytoplasmic DNA triggers ASC aggregation and recruits caspase-1, the central inflammasome effector enzyme, triggering cleavage of cytokines such as IL-1β and inducing GSDMD-mediated pyroptotic cell death. Restoration of AIM2 in bat cells led to intact ASC speck formation, but intriguingly resulted in a lack of caspase-1 or consequent IL-1β activation. We further identified two residues undergoing positive selection pressures in Pteropus alecto caspase-1 that abrogate its enzymatic function and are crucial in human caspase-1 activity. Functional analysis of another bat lineage revealed a targeted mechanism for loss of Myotis davidii IL-1β cleavage and elucidated an inverse complementary relationship between caspase-1 and IL-1β, resulting in overall diminished signaling across bats of both suborders. Thus we report strategies that additionally undermine downstream inflammasome signaling in bats, limiting an overactive immune response against pathogens while potentially producing an antiinflammatory state resistant to diseases such as atherosclerosis, aging, and neurodegeneration. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: G.G., M.A., A.T.I., and L.-F.W. conceived the study; M.A., A.T.I., and L.-F.W. provided resources and materials; G.G., L.B.L., and M.A. performed experiments; G.G., M.A., F.Z., and D.L. analyzed the data; and G.G., M.A., D.L., A.T.I., and L.-F.W. wrote the manuscript with input from all authors. 1G.G. and M.A. contributed equally to this work. Edited by Vishva M. Dixit, Genentech, San Francisco, CA, and approved September 14, 2020 (received for review February 21, 2020) |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.2003352117 |