Evolutionary loss of inflammasomes in carnivores to facilitate carriage of zoonotic infections

Digby, Z.; Rooney, J.; Boyle, J.P.; Bibo-Verdugo, B.; Pickering, R.; Webster, S.J.; Monie, T.P.; Hopkins, L.J.; Kayagaki, N.; Salvesen, G.S.; Warming, S.; Weinert, L.; Bryant, C.E.

Zoonotic infections, such as COVID-19, reside in animal hosts before jumping species to humans. The Carnivora, like mink, carry many zoonoses yet how diversity in host immune genes across species impact upon pathogen carriage are poorly understood. Here we describe a progressive evolutionary downregulation of pathogen sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerisation domain leucine rich repeat receptors (NLRs), acquisition of a unique caspase−1/−4 effector fusion protein that processes gasdermin D pore formation without inducing lytic cell death and the formation of an NLRP3-caspase-8 containing inflammasome that inefficiently processes interleukin-1β (IL-1β). Inflammasomes regulate gut immunity, but the carnivorous diet is antimicrobial suggesting a tolerance to the loss of these immune pathways. The consequences of systemic inflammasome downregulation, however, can reduce the host sensing of specific pathogens such that they can reside undetected in the Carnivora.