IL-19介导中性粒细胞免疫应答功能低下在流感继发细菌性肺炎中的作用机制及临床价值研究

In the clinic, secondary bacterial pneumonia after influenza infection accounts for approximately 90% death of influenza patients. After influenza virus infection, influenza-induced decrease of neutrophil immune responses is critical for the development of postinfluenza bacterial pneumonia. However, the molecular mechanisms regulating the decrease of neutrophil immune responses during influenza remain unknown. IL-19 is a newly described immunoregulatory cytokine. Our previous work has demonstrated that the expression of IL-19 was aberrantly enhanced after influenza infection, and IL-19 could inhibit anti-bacterial immune functions of neutrophils. Therefore, we hypothesized that the aberrantly increased IL-19 after influenza could inhibit the host immune responses of neutrophils, leading to the impairment of pulmonary immunity, and bacteria would thus evade host immune defense, finally resulting in the development of secondary bacterial pneumonia. This project will take IL-19-/- knockout mice and neutrophils to elucidate the role of IL-19-mediated decrease of neutrophil immune responses in the development of secondary bacterial pneumonia after influenza and its potential intracellular signaling pathways by use of FACS sorting, antibody blockade, gene chip and EMSA and CHIP, etc. We will also investigate the clinical significance of IL-19 in the development of postinfluenza bacterial pneumonia by using a large cohort of clinical samples from influenza patients. This work will definitely have important implications for the development of novel immunomodulatory targets in diagnosing and treating influenza infection.

临床上，流感继发细菌性肺炎是导致约90%流感患者死亡的原因。流感病毒感染后，宿主中性粒细胞免疫应答功能减低是继发细菌性肺炎发病的基础，但分子机制尚不清楚。IL-19是一种新型免疫调控分子，我们预实验发现其在流感病毒感染后异常表达增高，且IL-19可诱导中性粒细胞抗菌免疫应答功能减低。由此提出“流感病毒感染后，IL-19表达异常增高，IL-19进而诱导中性粒细胞免疫应答功能减低，肺脏区域免疫稳态被破坏，细菌逃逸宿主抗菌免疫反应”的科学假说。本课题拟以IL-19基因敲除小鼠和中性粒细胞等为研究模型，通过流式细胞分析、抗体阻断、表达谱芯片、EMSA和CHIP等技术，在分子、细胞和动物水平上揭示“IL-19介导中性粒细胞免疫应答功能减低”在流感继发细菌性肺炎中的作用及分子信号机制，并采用大宗临床样本明确IL-19表达与流感继发细菌感染的关联及其临床意义，为其诊治研究提供新型免疫靶标。

流感继发细菌性肺炎是导致流感患者死亡的最主要原因，迫切需要发现新的诊疗靶点以提高流感患者的生存率。本项研究中，我们首次发现巨噬细胞凋亡抑制分子（AIM/CD5L）可作为流感病毒感染和细菌感染的一种鉴别诊断生物标志物（J Infect 2022），入院时血清中AIM的浓度越高，患者细菌性感染的可能性就越大且发生死亡的风险也越高（J Infect 2020）；揭示细胞因子IL-34是流感病毒感染导致肺损伤的一种重要炎症分子，阻断IL-34可对重症流感肺炎有治疗作用（ Crit Care 2021）；阐明了细胞因子IL-27破坏肺脏免疫稳态的新机制，IL-27通过抑制IFN-γ表达促进侵袭性肺曲霉菌感染（Am J Respir Cell Mol Biol 2020）；报道了抑瘤素M （OSM）可作为细菌性肺炎和脓毒症患者死亡风险评估的一种新型生物标志物，阻断OSM可逆转细菌性脓毒症导致的肺损伤（J Infect Dis 2020）。总之，上述研究从新的角度揭示了流感病毒感染和细菌性肺炎发病的新机制，为其诊断和治疗提供了新型免疫靶标。