%0 Journal Article %A Coraline Chéneau %A Karsten Eichholz %A Tuan Hiep Tran %A Thi Thu Phuong Tran %A Océane Paris %A Corinne Henriquet %A Martine Pugniere %A Eric J Kremer %T Lactoferrin retargets adenoviruses to TLR4 to induce an abortive NLRP3-associated pyroptotic response in human dendritic cells %D 2020 %R 10.1101/2020.06.03.131664 %J bioRxiv %P 2020.06.03.131664 %X Despite decades of investigations, we still poorly grasp the immunogenicity of human adenovirus (HAdV)-based vaccines in humans. In this study, we explored the role of lactoferrin, which belong to the alarmin subset of antimicrobial peptides that provide immediate direct and indirect activity against a range of pathogens following a breach in tissue homeostasis. Lactoferrin is a globular, iron-sequestering, glycoprotein that can increase HAdV infection and maturation of antigen-presenting cells. However, the mechanism by which HAdV-lactoferrin complexes induce maturation is unknown. We show that lactoferrin redirects HAdVs from species B, C, and D to toll-like receptor 4 (TLR4) complexes on human mononuclear phagocyte. TLR4-mediated internalization induces an abortive NLRP3-associated pyroptotic response inducing pro-inflammatory cytokine release and disrupting plasma membrane integrity without cell death. These data impact our understanding of the immunogenicity of HAdV-based vaccines and may provide ways to increase their efficacy. %U https://www.biorxiv.org/content/biorxiv/early/2020/06/03/2020.06.03.131664.full.pdf