Evolutionary loss of inflammasomes in the Carnivora and implications for the carriage of zoonotic infections
Zsofi Digby,
Panagiotis Tourlomousis,
James Rooney,
Joseph P. Boyle,
Betsaida Bibo-Verdugo,
Robert J. Pickering,
Steven J. Webster,
Thomas P. Monie,
Lee J. Hopkins,
Nobuhiko Kayagaki,
Guy S. Salvesen,
Soren Warming,
Lucy Weinert,
Clare E. Bryant
Affiliations
Zsofi Digby
University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK
Panagiotis Tourlomousis
University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK
James Rooney
University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK
Joseph P. Boyle
University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK
Betsaida Bibo-Verdugo
Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines, La Jolla, CA 92037, USA
Robert J. Pickering
University of Cambridge, School of Clinical Medicine, Box 111, Cambridge Biomedical Campus, Cambridge CB2 0SP, UK
Steven J. Webster
University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK
Thomas P. Monie
University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK
Lee J. Hopkins
University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK; University of Cambridge, School of Clinical Medicine, Box 111, Cambridge Biomedical Campus, Cambridge CB2 0SP, UK
Nobuhiko Kayagaki
Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA
Guy S. Salvesen
Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines, La Jolla, CA 92037, USA
Soren Warming
Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA
Lucy Weinert
University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK
Clare E. Bryant
University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK; University of Cambridge, School of Clinical Medicine, Box 111, Cambridge Biomedical Campus, Cambridge CB2 0SP, UK; Corresponding author
Summary: 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.
