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

• DOI: 10.15252/embj.2018101365
• Publication Date: 2019-08-30T06:32:00Z
• Authors: Larisa I Labzin; Maria Bottermann; Pablo Rodriguez‐S...; Stian Foss; Jan Terje Andersen; Marina Vaysburd; Dean Clift; Leo C James
• Keywords: AIM2; Pyroptosis

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