Antibody and DNA sensing pathways converge to activate the inflammasome during primary human macrophage infection

TLDR

Inflammasomes are potent innate immune signalling complexes that couple cytokine release with pro‑inflammatory cell death, yet pathogens have evolved strategies to evade this cell‑autonomous system. The study shows how antibodies combine with innate sensors in primary human macrophages to detect viral infection and activate the inflammasome. Antibody binding of adenovirus induces lysosomal damage that activates NLRP3 and IL‑1β release, while antibody‑coated viruses that escape into the cytosol are intercepted by TRIM21 and cGAS, triggering NLRP3 inflammasome formation and NF‑κB activation. Antibody opsonisation of virions activates macrophages via lysosomal damage–induced NLRP3 inflammasome and IL‑1β release, enhancing virion capture without infection and causing cell death, while antibody‑coated viruses that escape into the cytosol are intercepted by TRIM21 and cGAS, triggering a second NLRP3 inflammasome and NF‑κB pathway that drives dose‑dependent IL‑1β and TNF secretion without cell death, underscoring the cooperative role of multiple sensing networks in exposing viruses to the inflammasome pathway, especially when pre‑existing immunity is present.

Abstract

Inflammasomes are potent innate immune signalling complexes that couple cytokine release with pro-inflammatory cell death. However, pathogens have evolved strategies to evade this cell autonomous system. Here, we show how antibodies combine with innate sensors in primary human macrophages to detect viral infection and activate the inflammasome. Our data demonstrate that antibody opsonisation of virions can activate macrophages in multiple ways. In the first, antibody binding of adenovirus causes lysosomal damage, activating NLRP3 to drive inflammasome formation and IL-1β release. Importantly, this mechanism enhances virion capture but not infection and is accompanied by cell death, denying the opportunity for viral replication. Unexpectedly, we also find that antibody-coated viruses, which successfully escape into the cytosol, trigger a second system of inflammasome activation. These viruses are intercepted by the cytosolic antibody receptor TRIM21 and the DNA sensor cGAS. Together, these sensors stimulate both NLRP3 inflammasome formation and NFκB activation, driving dose-dependent IL-1β and TNF secretion, without inducing cell death. Our data highlight the importance of cooperativity between multiple sensing networks to expose viruses to the inflammasome pathway, which is particularly important for how our innate immune system responds to infection in the presence of pre-existing immunity.