Pulmonary defense against aspergillus fumigatus

描述（由申请人提供）：由霉菌烟曲霉引起的侵袭性肺曲霉病已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，而且在不被认为是经典免疫功能低下的个体中。对A.烟曲霉涉及肺泡巨噬细胞的炎症反应的初始波，随后是嗜中性粒细胞的寻找和破坏使命。我们先前已经证明β-葡聚糖受体Dectin-1介导肺泡巨噬细胞（AM）对A.（Steele等，PLoS Pathog 1：e42，2005年12月），并且自从最近一次对该提议进行综述（2009年2月）以来，我们现在已经报道了Dectin-1缺陷的小鼠显示出对烟曲霉的固有易感性。烟曲霉肺部感染（Werner等人J Immunol 182：4938-4946，2009年4月）。最近一个有趣的发现是观察到“先天性IL-17”是抗A.（1）Dectin-1基因敲除小鼠在A.（2）IL-17中和抗体处理的WT小鼠对A.烟曲霉感染我们现在通过细胞内细胞因子染色显示，A.令人惊讶的是，在烟曲霉攻击中产生IL-17的细胞不是淋巴源的，而是髓样CD 11b+和CD 11 c+细胞群，其以Dectin-1依赖性方式产生IL-17。在其他数据中，我们表明IL-6和TGF-β，这是诱导Th 17细胞所必需的，在暴露于A的Dectin-1 KO小鼠的肺中并没有以较低的水平产生。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A.烟曲霉攻击，趋化因子CXCL 12/SDF-1和CCL 2/MCP-1也是如此。这些结果表明，Dectin-1可以控制A.通过产生IL-17相关的诱导细胞因子或产生对于将产生IL-17的细胞募集到肺中所必需的趋化因子，可以抑制烟曲霉暴露。最后，发现Th 17/IL-17相关细胞因子IL-22高度依赖于Dectin-1在肺中的表达。因此，我们假设最佳的IL-17介导的防御A。烟曲霉毒素依赖于β葡聚糖受体Dectin-1。以下具体目的将验证我们的假设：（1）鉴定A.（2）确定A.（3）确定IL-17诱导（IL-21/IL-23）、募集（SDF-1/MCP-1）和信号传导（IL-22）通路相关的介质是否调节肺宿主对A.烟熏。 公共卫生相关性：我们的数据表明，Dectin-1 β-葡聚糖受体通过控制可能最终需要清除A.肺里的烟曲霉菌本研究将进一步探讨先天性IL-17的细胞来源、该细胞群产生的Dectin-1依赖性机制以及IL-17家族成员是否能调节宿主对A.烟熏。

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. PUBLIC HEALTH RELEVANCE: Our data indicate that the Dectin-1 beta-glucan receptor is essential for immunity against Aspergillus fumigatus, the etiological agent of invasive pulmonary aspergillosis, by controlling an "innate IL-17" pathway that may be ultimately required for clearance of A. fumigatus from the lungs. Studies in this proposal will further characterize the cellular source of innate IL-17, the Dectin-1 dependent mechanisms for the generation of this cell population and whether IL-17 family members can modulate host defense against A. fumigatus.