The protective function of Interleukin-3 in secondary viral pneumonia during the immunosuppressive phase of sepsis

脓毒症是一种危及生命的临床综合征，与宿主对感染的反应有关。它可以分为过度炎症阶段，然后是免疫抑制阶段。因此，宿主对感染的反应不仅是一个立即和局部的过程，而且是一个涉及各种细胞类型的复杂的时间和空间划分事件。“炎性”细胞因子的初始释放诱导新细胞因子的产生和释放，引起细胞和器官损伤，并最终死亡。在随后的免疫抑制阶段，患者对医院感染和病毒再活化更敏感，这导致器官衰竭并最终导致死亡。Science，2015）。然而，IL-3在脓毒症（继发性病毒性肺炎）免疫抑制阶段的作用尚不清楚。我们假设IL-3激活CD 123+肺上皮细胞，导致CXCL 12介导的产生1型干扰素的循环成熟浆细胞样树突状细胞（pDC）易位到肺实质中，从而在脓毒症的免疫抑制阶段防止继发性病毒性肺炎。我们的假设是基于几个未发表的数据：在脓毒性免疫抑制期间继发性病毒性肺炎的模型中，与对照相比，IL-3-/-小鼠（i）对继发性病毒性肺炎更敏感;（ii）脾和肺中的pDC减少;（iii）肺中的1型干扰素水平减少;（iv）肺中的病毒载量增加;（v）未显示CXCL 12（一种吸引白细胞的趋化因子）的增加;（vi）血清IL-3水平降低的患者发生继发性病毒性肺炎的风险增加。我们将使用基因敲除动物模型、复杂的外科技术以及经典的分子和细胞生物学工具来验证这一假设。该项目很重要，因为它基于强大的表型并具有明确的翻译潜力：IL-3可被视为治疗病毒性肺炎的治疗靶点，而不仅仅是在免疫抑制和脓毒症的背景下。该项目具有创新性，因为它探索了炎症性疾病期间IL-3的生物学，具有探索败血症和病毒感染新治疗策略的潜力。

Sepsis is a life-threatening clinical syndrome related to the host response to infection. It can be divided into a phase of excessive inflammation followed by a phase of immunosuppression. The host response to infection is therefore not only an immediate and local process but a complex time- and space-compartmentalized event involving various cell types. The initial release of “inflammatory” cytokines induces new cytokine production and their release, causing cell and organ damage, and finally death. During the following immunosuppressive phase, patients are more sensitive to nosocomial infections and viral reactivation, which contributes to organs failure and finally, to death.Recently, we identified Interleukin-3 (IL-3) as a key modulator during acute inflammation in sepsis (Weber et al., Science, 2015). However, IL-3’s role in the following immunosuppressive phase during sepsis, in which secondary viral pneumonia occur, remains unclear. We hypothesise that IL-3 activates CD123+ lung epithelial cells resulting in the CXCL12 mediated translocation of type 1 interferon producing circulating mature plasmacytoid dendritic cells (pDCs) into the lung parenchyma, thus protecting against secondary viral pneumonia during the immunosuppressive phase in sepsis. Our hypothesis is based on several unpublished data: in a model of secondary viral pneumonia during septic immunosuppression, and as compared to controls, IL-3–/– mice are (i) more susceptible to secondary viral pneumonia; (ii) have reduced pDCs in the spleen and the lungs; (iii) have reduced type 1 interferon levels in the lungs; (iv) have increased viral load in the lungs; (v) do not show an increase of CXCL12, a chemokine that attracts leukocytes; and (vi) patients with reduced IL-3 serum levels have an increased risk for the development of secondary viral pneumonia.We will test the hypothesis using gene-knockout animal models, sophisticated surgical techniques, and classical molecular and cell biology tools. The project is important because it is based on a strong phenotype and has clear translational potential: IL-3 may be considered as a therapeutic target for the treatment of viral pneumonia, not only in the context of immunosuppression and sepsis. The project is innovative because it explores the biology of IL-3 during inflammatory disease with the potential of exploring new therapeutic strategies for sepsis and viral infections.