ILC2-Mediated Protection from Acute Lung Infection

项目摘要 关于新近描述的2型固有淋巴样细胞(ILC2)群体的信息有限 这些细胞的调节，以及它们在预防急性呼吸道感染方面的作用。我们有 现在发现干扰素-γ对ILC2免疫功能有负面调节作用，而干扰素-γ表达缺陷的动物 表现出对初级H1N1大流行病毒感染和继发性H1N1大流行病毒感染的抵抗力增强 肺炎球菌感染。病毒感染的干扰素-γ-/-小鼠ILC2活性增强的同时伴随着降低 肺组织炎症和肺IL-5、双调节蛋白和嗜酸性粒细胞表达增加，但NO 病毒负担的变化。重要的是，在干扰素-γ中和后观察到的增强保护作用没有观察到 ILC2缺陷小鼠。这项建议中的研究旨在现在确定ILC2在 对流感和继发性细菌感染的抗药性。根据我们的初步数据，我们假设 干扰素-γ信号减弱ILC2先天效应功能并导致组织减少 动态平衡和寄主生存。为了测试这个概念，我们将利用几个独特的资源，包括 缺乏ILC2、嗜酸性粒细胞表达和转化生长因子-βIIR信号的新品系小鼠，以及我们的 在研究宿主-病原体相互作用方面有丰富的经验。目标是首次确定：1) ILC2s在介导对CA04流感感染的抵抗力中的作用；2)ILC2s在调节中的作用 对流感后继发细菌感染的易感性。最终目标是获得一个 了解预防急性呼吸道感染的过程，并利用 为影响预防和治疗流感的临床方法而获得的信息和 相关的继发性细菌感染。

Project Summary There is only limited information about the newly described type 2 innate lymphoid cell (ILC2) population in the lung, the regulation of these cells, and their impact on protection against acute respiratory infections. We have now found that IFN-γ negatively regulates ILC2 immune function and that animals deficient in IFN-γ expression demonstrate increased resistance to both primary H1N1 pandemic virus infection as well as secondary pneumococcal infection. Enhanced ILC2 activity in viral-infected IFN-γ-/- mice is accompanied by decreased lung tissue inflammation and increased expression of pulmonary IL-5, amphiregulin, and eosinophils, but no change in viral burden. Importantly, the increased protection seen after IFN-γ neutralization is not observed in ILC2-deficient mice. Studies in this proposal are designed to now determine the unique role of ILC2s in resistance to influenza and secondary bacterial infections. Based on our preliminary data, we hypothesize that IFN-γ signaling diminishes ILC2 innate effector function and leads to decreased tissue homeostasis and host survival. To test this concept, we will exploit several unique resources, including novel strains of mice that are deficient in ILC2s, eosinophil expression, and TGF-βIIR signaling, as well as our extensive experience in studying host-pathogen interactions. The aims are to determine for the first time: 1) the role of ILC2s in mediating resistance to CA04 influenza infection; and 2) the role of ILC2s in regulating susceptibility to secondary bacterial infections following influenza. The ultimate goal is to obtain an understanding of the processes responsible for protection against acute respiratory infection and to exploit the information obtained in order to influence clinical approaches for prevention and treatment of influenza and associated secondary bacterial infections.