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

Change log
Digby, Zsofi 
Tourlomousis, Panagiotis  ORCID logo  https://orcid.org/0000-0002-6152-8066
Rooney, James 
Boyle, Joseph P 
Bibo-Verdugo, Betsaida 

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.

Carnivora, NLRC4, NLRP3, caspase 1, caspase 11, caspase 4, inflammasome, Animals, Carnivora, Caspase 1, Caspase 8, Caspases, Initiator, Cell Death, Cell Line, Evolution, Molecular, Humans, Inflammasomes, Interleukin-1beta, Lipopolysaccharides, Macrophages, Mice, Mice, Inbred C57BL, NLR Proteins, Recombinant Fusion Proteins, Recombinant Proteins, Salmonella typhi, Zoonoses
Journal Title
Cell Rep
Conference Name
Journal ISSN
Volume Title
Elsevier BV
All rights reserved
Wellcome Trust (108045/Z/15/Z)
Wellcome Trust (109385/Z/15/Z)