Lactoferrin retargets adenoviruses to TLR4 to induce an abortive NLRP3-associated pyroptotic response in human dendritic cells

Cheneau, C.; Eichholz, K.; Tran, T. H.; Tran, T. T. P.; Paris, O.; Henriquet, C.; Pugniere, M.; Kremer, E. J.

doi:10.1101/2020.06.03.131664

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bioRxiv · 10.1101/2020.06.03.131664

Lactoferrin retargets adenoviruses to TLR4 to induce an abortive NLRP3-associated pyroptotic response in human dendritic cells

Cheneau, C.·Eichholz, K.·Tran, T. H.·Tran, T. T. P.·Paris, O.·Henriquet, C.·Pugniere, M.·Kremer, E. J.

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Abstract

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.

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Cheneau, C., Eichholz, K., Tran, T. H., Tran, T. T. P., Paris, O., Henriquet, C., Pugniere, M., Kremer, E. J.. 2020-06-03. Lactoferrin retargets adenoviruses to TLR4 to induce an abortive NLRP3-associated pyroptotic response in human dendritic cells. https://doi.org/10.1101/2020.06.03.131664

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