Alteration of Flt3-Ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to respiratory bacterial superinfection.
Alteration of Flt3-Ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to respiratory bacterial superinfection.
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DOI：
10.1371/journal.ppat.1007360
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发表时间：
2018-10
期刊：
影响因子：
6.7
通讯作者：
Faveeuw C
中科院分区：
文献类型：
--
作者：
Beshara R;Sencio V;Soulard D;Barthélémy A;Fontaine J;Pinteau T;Deruyter L;Ismail MB;Paget C;Sirard JC;Trottein F;Faveeuw C
继发性细菌感染导致甲型流感病毒（IAV）感染的发病率和死亡率过高。在IAV感染期间，肺完整性的破坏和抗菌免疫力的受损参与了细菌在肺外的定殖和传播。IAV感染的一个关键特征是肺髓样细胞的显著改变，其特征在于有害的炎性单核细胞的募集。我们在此报告，IAV感染导致肺常规树突状细胞（cDC）（cDC 1和cDC 2）的短暂减少，在感染后第7天达到峰值。在触发紧急单细胞生成的同时，IAV瞬时改变了骨髓中cDC的分化，cDC 1-biaised pre-DC特别受到影响。IAV感染期间cDC分化受损与I型干扰素（IFN）、IFN-γ、TNFα和IL-6无关，也不是由于cDC前体的内在功能障碍。cDC分化的改变与局部和全身Fms样酪氨酸激酶3配体（Flt 3-L）（一种关键的cDC分化因子）的产生下降相关。在IAV感染过程中，Flt 3-L的过表达促进了BM中cDC祖细胞的产生，补充了肺中的cDC，减少了炎性单核细胞的浸润，减轻了肺损伤。这与对继发性肺炎球菌感染的部分保护有关，如细菌传播减少和生存期延长所反映的。这些发现强调了远端病毒感染对BM中cDC发生的影响，并表明Flt 3-L可能在控制继发性感染中具有潜在的应用。继发性细菌感染是流感流行和大流行期间死亡的主要原因。急性感染触发骨髓细胞从骨髓（BM）向感染组织的动员，这一过程被称为紧急骨髓生成。流感感染导致肺髓样细胞区室的深刻改变，其特征在于炎性髓样细胞的募集。IAV感染对骨髓造血的影响尚待详细描述。在这里，我们报告说，流感感染导致肺中常规树突状细胞（cDC）数量减少（在第7天达到峰值），并严重损害BM中的DC分化，有利于单细胞生成。改变的cDC分化独立于促炎细胞因子，并且不是由于cDC前体的内在功能障碍。流感期间DC分化缺陷与关键cDC分化因子Fms样酪氨酸激酶3配体（Flt 3-L）的产生减少相关。流感期间Flt 3-L的过表达增加了BM cDC祖细胞的数量并恢复了肺cDC隔室。这种现象与肺部炎性单核细胞数量减少和肺损伤减少有关。重要的是，Flt 3-L过表达部分保护免受继发性肺炎球菌感染，其特征在于减少细菌负荷，改善病理结果和延长生存期。我们的研究结果为流感感染如何影响cDCs的分化提供了新的线索，并突出了Flt 3-L在迫切需要更好治疗的疾病中的潜在治疗价值。
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. Secondary bacterial infections constitute a leading cause of mortality during influenza epidemics and pandemics. Acute infections trigger the mobilization of myeloid cells from the bone marrow (BM) to the infected tissues, a process referred to as emergency myelopoiesis. Influenza infection leads to a profound alteration in the pulmonary myeloid cell compartment characterized by the recruitment of inflammatory myeloid cells. The consequences of IAV infection on BM myelopoiesis have yet to be described in detail. Here, we report that influenza infection leads to reduced number of conventional dendritic cells (cDC) in the lungs (with a peak at day 7) and severely impairs DC differentiation in the BM, for the benefit of monopoiesis. The altered cDC differentiation was independent of pro-inflammatory cytokines and was not due to an intrinsic dysfunction of cDC precursors. Defective DC differentiation during influenza was associated with a decrease in the production of the key cDC differentiation factor, Fms-like tyrosine kinase 3 ligand (Flt3-L). Overexpression of Flt3-L during influenza enhanced the number of BM cDC progenitors and restored lung cDC compartment. This phenomenon was associated with a lowered number of lung inflammatory monocytes and reduced lung damages. Importantly, Flt3-L overexpression partially protected against secondary pneumococcal infection characterized by reduced bacterial loads, improved pathological outcomes and prolonged survival. Our results provide new clues as to how influenza infection influences the differentiation of cDCs, and highlight the potential therapeutic value of Flt3-L in a disease in desperate need of better treatments.
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