Evolutionary loss of inflammasomes in the Carnivora and implications for the carriage of zoonotic infections

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 downr...

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Bibliographic Details
Published in:	Cell reports (Cambridge) Vol. 36; no. 8; p. 109614
Main Authors:	Digby, Zsofia, Tourlomousis, Panagiotis, Rooney, James, Boyle, Joseph P., Bibo-Verdugo, Betsaida, Pickering, Robert J., Webster, Steven J., Monie, Thomas P., Hopkins, Lee J., Kayagaki, Nobuhiko, Salvesen, Guy S., Warming, Soren, Weinert, Lucy, Bryant, Clare E.
Format:	Journal Article
Language:	English
Published:	Elsevier Inc 24-08-2021 Cell Press Elsevier
Subjects:	Carnivora caspase 1 caspase 11 caspase 4 inflammasome NLRC4 NLRP3 Carnivora inflammasome caspase 11 NLRP3 caspase 1 NLRC4 caspase 4
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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. [Display omitted] •Carnivorans lack key NLRs and express a unique caspase-1/-4 hybrid protein•This protein is defective in mediating activation of common inflammasome pathways•What little activity occurs is driven by caspase-8, rather than caspase-1/-4 Species of the order Carnivora have evolutionarily acquired the expression of a unique caspase-1/-4 hybrid protein. Digby et al. show that this protein is a poor mediator of NLRP3- and caspase-4-dependent inflammasome activation. This downregulation in inflammasome pathways could impair pathogen detection and facilitate transmission of zoonotic infections.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally Lead contact
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2021.109614