Date Published: October 29, 2018
Publisher: Public Library of Science
Author(s): Ranin Beshara, Valentin Sencio, Daphnée Soulard, Adeline Barthélémy, Josette Fontaine, Thibault Pinteau, Lucie Deruyter, Mohamad Bachar Ismail, Christophe Paget, Jean-Claude Sirard, François Trottein, Christelle Faveeuw, Andrea J. Sant.
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.
Influenza A viruses (IAV) are responsible for acute respiratory tract diseases and represent a threat to human health worldwide. Infection with IAV is frequently complicated by secondary bacterial infections; these typically occur between 4 to 14 days after the primary IAV infection (depending on the pathogenicity of the virus and the host’s immune system). In the context of influenza, physical disorders (e.g. impaired barrier function) and immunological disorders are the two main causes of enhanced susceptibility to bacterial infections (for reviews, [1, 2]). Upon IAV infection, the proportion and number of myeloid cells in the lungs change markedly. Indeed, inflammatory monocytes and monocyte-derived dendritic cells (DCs) are strongly recruited. Although monocyte-derived DCs are important for locally boosting the IAV-specific CD8+ T cell response [3–6], inflammatory monocytes exert a harmful pro-inflammatory effect in the lungs [7–10]. Regarding pulmonary sentinel cells, whether alveolar macrophages are depleted or not upon IAV infection remains an open question [6, 11, 12]. A recent study suggested that alveolar macrophages depletion/persistence upon IAV infection is largely dependent of mouse genetic background and infection conditions . The situation is less clear for conventional DCs (cDCs), a family of critical sentinel cells composed by two main subpopulations in the lungs, namely cDC1 and cDC2. We recently reported a drastic decrease of total cDCs in IAV-infected mice . Prior observations rather suggested a recruitment of cDC2 upon infection [4, 5, 11]. Regarding cDC1, whether they are depleted or not during the course of IAV infection remains unclear [4, 5, 11]. Differences in immunophenotyping strategies and in experimental design (i.e., viral dose/strain or mouse genetic background) could account for contrasting conclusions.
The regulation of DC homeostasis during infection is of major importance because DCs are essential for the initiation of innate and acquired immune responses. Many studies reported DC depletion during systemic infections such as sepsis (for a review, ). Along with impaired DC function, this DC depletion is a major cause of immunosuppression and predisposition to bacterial infections [57, 58]. In the present study, we investigated the impact of local (pulmonary) viral infection on cDC homeostasis. Our observation of a transient depletion of cDCs – cDC1 and cDC2 – in the lungs of IAV-infected mice contrasts with previous reports showing a recruitment of cDC2 and the absence or a slight decrease of cDC1 [4, 5, 11]. The methodology used in the current report, i.e. use of anti-CD64 mAb which discriminates monocyte-derived DCs and cDCs, differed from these prior studies and could explain the different conclusions. Importantly, we showed for the first time that IAV infection strongly affects cDC progenitor differentiation in the BM, a phenomenon associated with an impaired production of Flt3-L. Overexpression of Flt3-L during IAV infection enhanced cDC differentiation in the BM, restored the cDC counts in the lungs and lowered inflammatory monocytes’ infiltration and lung injury. Importantly, Flt3-L overexpression provided partial protection against secondary bacterial infection.