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Alteration of Flt3-Ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to respiratory bacterial superinfection

Abstract : Secondary bacterial infections contribute to the excess morbidity and mortality of influenza A virus (IAV) infection. Disruption of lung integrity and impaired antibacterial immunity during IAV infection participate in colonization and dissemination of the bacteria out of the lungs. One key feature of IAV infection is the profound alteration of lung myeloid cells, characterized by the recruitment of deleterious inflammatory monocytes. We herein report that IAV infection causes a transient decrease of lung conventional dendritic cells (cDCs) (both cDC1 and cDC2) peaking at day 7 post-infection. While triggering emergency monopoiesis, IAV transiently altered the differentiation of cDCs in the bone marrow, the cDC1-biaised pre-DCs being particularly affected. The impaired cDC differentiation during IAV infection was independent of type I interferons (IFNs), IFN-γ, TNFα and IL-6 and was not due to an intrinsic dysfunction of cDC precursors. The alteration of cDC differentiation was associated with a drop of local and systemic production of Fms-like tyrosine kinase 3 ligand (Flt3-L), a critical cDC differentiation factor. Overexpression of Flt3-L during IAV infection boosted the cDC progenitors' production in the BM, replenished cDCs in the lungs, decreased inflammatory monocytes' infiltration and lowered lung damages. This was associated with partial protection against secondary pneumococcal infection, as reflected by reduced bacterial dissemination and prolonged survival. These findings highlight the impact of distal viral infection on cDC genesis in the BM and suggest that Flt3-L may have potential applications in the control of secondary infections.
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Submitted on : Tuesday, October 5, 2021 - 10:23:14 AM
Last modification on : Tuesday, October 19, 2021 - 11:56:32 PM

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Ranin Beshara, Valentin Sencio, Daphnée Soulard, Adeline Barthélémy, Josette Fontaine, et al.. Alteration of Flt3-Ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to respiratory bacterial superinfection. PLoS Pathogens, Public Library of Science, 2018, 14 (10), pp.e1007360. ⟨10.1371/journal.ppat.1007360⟩. ⟨hal-03365078⟩

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