PT  - JOURNAL ARTICLE
AU  - Coraline Chéneau
AU  - Karsten Eichholz
AU  - Tuan Hiep Tran
AU  - Thi Thu Phuong Tran
AU  - Océane Paris
AU  - Corinne Henriquet
AU  - Martine Pugniere
AU  - Eric J Kremer
TI  - Lactoferrin retargets adenoviruses to TLR4 to induce an abortive NLRP3-associated pyroptotic response in human dendritic cells
AID  - 10.1101/2020.06.03.131664
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.03.131664
4099  - http://biorxiv.org/content/early/2020/06/03/2020.06.03.131664.short
4100  - http://biorxiv.org/content/early/2020/06/03/2020.06.03.131664.full
AB  - 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.