1. Evolutionary loss of inflammasomes in the Carnivora and implications for the carriage of zoonotic infections.
- Author
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Digby Z, Tourlomousis P, Rooney J, Boyle JP, Bibo-Verdugo B, Pickering RJ, Webster SJ, Monie TP, Hopkins LJ, Kayagaki N, Salvesen GS, Warming S, Weinert L, and Bryant CE
- Subjects
- Animals, Caspase 1 genetics, Caspase 1 metabolism, Caspase 8 metabolism, Caspases, Initiator genetics, Caspases, Initiator metabolism, Cell Death, Cell Line, Humans, Interleukin-1beta metabolism, Lipopolysaccharides pharmacology, Macrophages cytology, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred C57BL, NLR Proteins genetics, NLR Proteins metabolism, Recombinant Fusion Proteins biosynthesis, Recombinant Fusion Proteins genetics, Recombinant Proteins genetics, Recombinant Proteins metabolism, Salmonella typhi pathogenicity, Zoonoses immunology, Zoonoses parasitology, Carnivora metabolism, Evolution, Molecular, Inflammasomes metabolism, Zoonoses pathology
- Abstract
Zoonotic pathogens, such as COVID-19, reside in animal hosts before jumping species to infect humans. The Carnivora, like mink, carry many zoonoses, yet how diversity in host immune genes across species affect pathogen carriage is poorly understood. Here, we describe a progressive evolutionary downregulation of pathogen-sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerization domain leucine-rich repeat receptors (NLRs), acquisition of a unique caspase-1/-4 effector fusion protein that processes gasdermin D pore formation without inducing rapid lytic cell death, and the formation of a caspase-8 containing inflammasome that inefficiently processes interleukin-1β. Inflammasomes regulate gut immunity, but the carnivorous diet has antimicrobial properties that could compensate for the loss of these immune pathways. We speculate that the consequences of systemic inflammasome downregulation, however, can impair host sensing of specific pathogens such that they can reside undetected in the Carnivora., Competing Interests: Declaration of interests N.K. and S.W. are employees of Genentech, Z.D. is employed by Nodthera, L.J.H. is employed by Wren Pharmaceuticals, and S.J.W is employed by Cell Press. C.E.B. serves on the Scientific Advisory Board of Lightcast, NodThera, and Related Sciences and consults for Janssen., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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