Adenovirus-α-defensin complexes induce NLRP3-associated maturation of human phagocytes via TLR4 engagement

Intramuscular delivery of human adenovirus (HAdV)-based vaccines leads to rapid recruitment of neutrophils, which then release antimicrobial peptides/proteins (AMPs). How these AMPs influence vaccine efficacy over the subsequent 24 hr is poorly understood. In this study, we asked if human neutrophil protein 1 (HNP-1), an α-defensin that influences the direct and indirect innate immune responses to a range of pathogens, impacts the innate response of human phagocytes to three HAdV species/types (HAdV-C5, -D26, -B35). We show that HNP-1 binds to the capsids, redirects HAdV-C5, -D26, -B35 to Toll-like receptor 4 (TLR4), which leads to internalization, an NLRP3-mediated inflammasome response, and IL-1β release. Surprisingly, IL-1β release was not associated with notable disruption of plasma membrane integrity. These data further our understanding of HAdV innate immunogenicity and may provide pathways to extend HAdV-based vaccines efficacy.