REDUCED CASPASE-1 ACTIVITY AND IL-1β CLEAVAGE CONTRIBUTE TO MULTILEVEL DAMPENING OF BAT INFLAMMASOME ACTIVATION

Abstract

Bats have emerged as reservoir hosts for diverse lethal zoonotic viruses such as the recent SARS-CoV-2, yet suffer minimal clinical disease from these pathogens. Recent studies have found that multiple sensors of the innate immune inflammasome pathway are dampened in bats, including a complete genomic loss of AIM2 and reduced NLRP3 activation. Our study investigated the functional implications of absent AIM2 sensor in bats via its reconstitution in a bat cellular environment. We observed that the downstream caspase-1 activation, cell death and IL-1β secretion were not induced despite AIM2 restoration and ASC speck formation, and therefore hypothesized that caspase-1 and/or IL-1β were deficient in bats. Two key residues from caspase-1 of Pteropus bat were identified to be responsible for the abrogation of its activity, which is restored by substitution with the equivalent human caspase-1 amino acid residues. In contrast, in another bat (Myotis davdii) with intact caspase-1 activity, non-synonymous substitutions in the downstream substrate IL-1β resulted in its deficient cleavage and secretion. Thus, this study reports novel strategies targeting multiple levels of the inflammasome pathway with which bats have evolved to diminish activation and signaling.