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

PLoS Pathog. 2018 Oct 29;14(10):e1007360. doi: 10.1371/journal.ppat.1007360. eCollection 2018 Oct.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / microbiology
  • Dendritic Cells / virology
  • Influenza A virus / immunology*
  • Lung / immunology*
  • Lung / microbiology
  • Lung / virology
  • Male
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orthomyxoviridae Infections / complications
  • Orthomyxoviridae Infections / virology*
  • Pneumococcal Infections / immunology*
  • Pneumococcal Infections / microbiology
  • Pneumococcal Infections / virology
  • Receptor, Interferon alpha-beta / physiology
  • Streptococcus pneumoniae / immunology
  • Superinfection / immunology*

Substances

  • Cytokines
  • Ifnar1 protein, mouse
  • Membrane Proteins
  • flt3 ligand protein
  • Receptor, Interferon alpha-beta

Grants and funding

This work was supported by Inserm, CNRS, University of Lille, l'Institut Pasteur de Lille and grants from the région des Hauts-de-France and the state of Minais Gerais/FAPEMIG (Franco-Brazilian call 2014-2015, FLUMICROBIOT) and l’Agence Nationale de la Recherche (AAP générique 2017, ANR-17-CE15-0020-01, ACROBAT) and la Structure Fédérative Maladies Infectieuses, Inflammatoires Immunitaires (SF3i – FED 4258). CF, JCS and CP were supported by Inserm. FT was supported by CNRS. RB was a recipient of a doctoral fellowship from the National Council for Scientific Research of the Lebanese Republic (CNRS-L) and the Lebanese University, (CNRS-L/UL PhD award program). MBI was supported by the Doctoral School of Science and Technology in the Lebanese University. VS and AB were recipients of a doctoral fellowship from the Ministère de l’Education Nationale de la Recherche et Technique. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.