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

Zsofia Digby,Lee J Hopkins,Nobuhiko Kayagaki,Clare E Bryant,Robert J Pickering,Lucy Weinert,Joseph P Boyle,Thomas P Monie,Panagiotis Tourlomousis,Steven J Webster,Soren Warming,Betsaida Bibo-Verdugo,Guy S Salvesen,James Rooney

doi:10.1016/j.celrep.2021.109614

Zsofia Digby, Lee J Hopkins + Show 12 more

Open Access

https://doi.org/10.1016/j.celrep.2021.109614

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Abstract

SummaryZoonotic 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.

Highlights

Viral and bacterial zoonotic pathogens, such as coronavirus disease 2019 (COVID-19) and Salmonella species, can infect animal hosts in an asymptomatic or symptomatic manner, which may facilitate the transmission to humans
By comparing the distribution and evolution of inflammasome and cell death genes across the order Carnivora, we find a profound compromise in inflammasome functionality, caspasedependent lytic cell death pathways, and a critical loss of nucleotide-oligomerization domain leucine-rich repeat receptors (NLRs) genes
Analysis of dog gasdermin D shows that both domains are conserved and, the linker region is more divergent, the aspartate cleavage site is present (Wang et al, 2020), consistent with full functionality of this protein in the Carnivora

Summary

Introduction

Viral and bacterial zoonotic pathogens, such as coronavirus disease 2019 (COVID-19) and Salmonella species, can infect animal hosts in an asymptomatic or symptomatic manner, which may facilitate the transmission to humans. Comparative biology of animal immune systems and their links to infection susceptibility are less well understood. 49% of all carnivore species (e.g., mink, dogs), the highest proportion of any mammal order including bats, carry one or more unique zoonotic pathogens (Han et al, 2016). Whether this is because Carnivora are a large group of animals harboring many pathogens, so they carry proportionally more zoonoses (Mollentze and Streicker, 2020), or due to other factors such as differences in the immune system remains to be determined

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