Pulmonary defense against aspergillus fumigatus

描述（由申请人提供）：由烟曲霉引起的侵袭性肺曲霉病已经成为最严重的侵袭性真菌感染之一，不仅在不断扩大的免疫抑制患者群体中，而且在不被认为是典型免疫功能低下的个体中。针对烟曲霉的先天免疫涉及肺泡巨噬细胞的初始炎症反应，随后是中性粒细胞的寻找和破坏任务。我们之前已经证明β -葡聚糖受体Dectin-1介导肺泡巨噬细胞（AM）对体外烟曲霉的炎症反应（Steele等）。PLoS Pathog 1:e42 Dec. 2005)，自上次对该提案的审查（2009年2月）以来，我们现在报道缺乏Dectin-1的小鼠对烟曲霉肺部感染表现出固有的易感性（Werner等）。中华医学杂志，2009(4):344 - 344。最近，一个有趣的发现是观察到“先天IL-17”是烟曲霉抗性的核心组成部分：(1)Dectin-1 KO小鼠在烟曲霉攻击后不久肺部IL-17产生缺陷；(2)给予IL-17中和抗体的WT小鼠对烟曲霉感染敏感。我们现在通过细胞内细胞因子染色显示，烟熏菌攻击后肺中IL-17的主要细胞来源令人惊讶地不是淋巴细胞，而是髓系CD11b+和CD11c+细胞群，它们以依赖Dectin-1的方式产生IL-17。在其他数据中，我们发现IL-6和TGF-¿是诱导Th17细胞所必需的，在暴露于烟曲霉的Dectin-1 KO小鼠的肺部中并没有以较低的水平产生，这表明其他机制/介质负责Dectin-1依赖性IL-17的产生。反过来，新的数据表明，在烟曲霉攻击后，Dectin-1 KO小鼠中Th17/IL-17诱导细胞因子IL-21和Th17/IL-17维持细胞因子IL-23的产生减少，趋化因子CXCL12/SDF-1和CCL2/MCP-1也是如此。这些结果表明，Dectin-1可能通过产生IL-17相关的诱导细胞因子或产生将IL-17产生细胞募集到肺部所必需的趋化因子来控制烟曲霉暴露后肺中IL-17的水平。最后，我们发现Th17/IL-17相关的细胞因子IL-22高度依赖于Dectin-1在肺中的表达。因此，我们假设il -17介导的对烟曲霉的最佳防御依赖于β -葡糖素受体Dectin-1。以下特定目的将验证我们的假设：(1)确定烟熏假单胞菌暴露后肺中IL-17依赖的Dectin-1细胞来源；(2)确定烟熏假单胞菌暴露后肺中IL-17依赖的细胞特异性产生的机制；(3)确定与IL-17诱导（IL-21/IL-23）、募集（SDF-1/MCP-1）和信号通路（IL-22）相关的介质是否调节肺宿主对烟熏假单胞菌的防御。

DESCRIPTION (provided by applicant): Invasive pulmonary aspergillosis caused by the mold Aspergillus fumigatus has emerged as one of the most severe invasive fungal infections, not only in an expanding population of immunosuppressed patients, but also in individuals who are not considered classically immunocompromised. Innate immunity against A. fumigatus involves an initial wave of inflammatory reaction by alveolar macrophages followed by the seek-and- destroy mission of neutrophils. We have previously shown that the beta-glucan receptor Dectin-1 mediates alveolar macrophage (AM) inflammatory responses to A. fumigatus in vitro (Steele et al. PLoS Pathog 1:e42 Dec. 2005) and since the last review of this proposal (February 2009), we have now reported that mice deficient in Dectin-1 display an inherent susceptibility to A. fumigatus lung infection (Werner et al. J Immunol 182: 4938-4946, April 2009). A recent, intriguing finding was the observation that "innate IL-17" was a central component of resistance to A. fumigatus: (1) Dectin-1 KO mice had a defect in lung IL-17 production shortly after A. fumigatus challenge and (2) WT mice administered IL-17 neutralizing antibodies became susceptible to A. fumigatus infection. We now show by intracellular cytokine staining that the predominant cellular sources of IL-17 in the lungs after A. fumigatus challenge are surprisingly not lymphoid in origin, but rather myeloid CD11b+ and CD11c+ cell populations, which produce IL-17 in a Dectin-1 dependent manner. In other data, we show that IL-6 and TGF-¿, which are essential for the induction of Th17 cells, are not produced at lower levels in the lungs of Dectin-1 KO mice exposed to A. fumigatus, suggesting that other mechanisms/mediators are responsible for Dectin-1 dependent IL-17 production. In turn, new data indicate that production of the Th17/IL- 17 induction cytokine IL-21 and the Th17/IL-17 maintenance cytokine IL-23 are attenuated in Dectin-1 KO mice after A. fumigatus challenge, as are the chemokines CXCL12/SDF-1 and CCL2/MCP-1. These results suggest that Dectin-1 may control IL-17 levels in the lungs after A. fumigatus exposure via production of IL-17- associated induction cytokines or production of chemokines essential for the recruitment of IL-17-producing cells to the lungs. Finally, the Th17/IL-17 associated cytokine IL-22 was found to be highly dependent in Dectin-1 for its expression in the lungs. Therefore, we hypothesize that optimal IL-17-mediated defense against A. fumigatus is dependent on the beta glucan receptor Dectin-1. The following Specific Aims will test our hypothesis: (1) To identify the Dectin-1 dependent cellular source of IL-17 in the lungs after A. fumigatus exposure, (2) To identify the mechanism(s) responsible for Dectin-1 dependent, cell-specific production of IL-17 after A. fumigatus lung exposure and (3) To determine whether mediators associated with IL-17 induction (IL-21/IL-23), recruitment (SDF-1/MCP-1) and signaling (IL-22) pathways modulate lung host defense against A. fumigatus.