Dectin-1 and Invasive Pulmonary Aspergillosis

项目负责人/主要研究者（最后，第一，中间）：1 R 01 AI 068917 - 01 A2 PI姓名：STEELE，CHAD摘要造血干细胞或实体器官移植相关的免疫抑制导致侵袭性真菌感染的显著易感性，特别是由烟曲霉引起的感染。我们以前曾报道过，阻断β-葡聚糖受体Dectin-1的识别可以减弱肺泡巨噬细胞对A.离体培养。在这里，我们发现缺乏Dectin-1的免疫活性小鼠（Dectin-1-/-）对A.烟曲霉，在5天内表现出>80%的死亡率，最终是由于肺功能受损。攻击后24小时，Dectin-1-/-小鼠的促炎细胞因子和趋化因子产生受损，导致肺中性粒细胞募集减弱，随后出现不受控制的A.烟曲霉肺生长。组织学评估提供了进一步的证据，缺陷的中性粒细胞募集和异常的中性粒细胞识别A。Dectin-1-/小鼠中的烟曲霉毒素。体外研究表明，A.烟曲霉不能诱导来自Dectin-1-/-肺泡巨噬细胞的促炎反应，而Dectin-1-/-中性粒细胞不能杀死A.烟熏。总的来说，这些结果支持Dectin-1在产生巨噬细胞来源的中性粒细胞募集信号以及嗜中性粒细胞介导的肺A细胞抑制中的基本作用。烟熏。此外，我们在初步研究中进一步表明，IL-1和IL-1是抗A.烟曲霉菌总的来说，我们的数据支持Dectin-1是参与宿主对A.烟熏。因此，我们的中心假设是，Dectin-1 β葡聚糖受体是抗A.烟曲霉和成功的宿主防御侵袭性肺曲霉病。我们计划通过以下具体目的来验证我们的假设：（1）验证Dectin-1是抗A.（2）检验IL-1在抗烟曲霉免疫中的作用。烟熏。这些研究的结果将提供宝贵的洞察第一线防御机制，对A。并有望引导我们开发新的免疫策略，以增强宿主对烟曲霉的防御。易感染个体的烟曲霉菌。

Program Director/Principal Investigator (Last, First, Middle): 1R01AI068917 - 01A2 PI Name: STEELE, CHAD ABSTRACT Immunosuppression associated with hematopoietic stem cell or solid organ transplantation results in a significant predisposition to invasive fungal infections, particularly those caused by Aspergillus fumigatus. We have previously reported that interruption of recognition by the beta-glucan receptor Dectin-1 attenuated alveolar macrophage inflammatory responses to A. fumigatus in vitro. Here, we show that immunocompetent mice lacking Dectin-1 (Dectin-1-/-) are inherently sensitive to intratracheal challenge with A. fumigatus, exhibiting >80% mortality within 5 days, ultimately as a result of compromised lung function. Twenty-four hours after challenge, Dectin-1-/- mice had impaired proinflammatory cytokine and chemokine production which resulted in blunted lung neutrophil recruitment and subsequent uncontrolled A. fumigatus lung growth. Histological assessment provided further evidence for both defective neutrophil recruitment and aberrant neutrophil recognition of A. fumigatus in Dectin-1-/mice. In vitro studies indicated that A. fumigatus failed to induce proinflammatory responses from Dectin-1-/- alveolar macrophages whereas Dectin-1-/- neutrophils were unable to kill A. fumigatus. Collectively, these results support a fundamental role for Dectin-1 in the generation of macrophage-derived neutrophil recruitment signals as well as in neutrophil-mediated containment of pulmonary A. fumigatus. Moreover, we further show in preliminary studies that IL-1 and IL-1 are essential mediators of innate immunity against A. fumigatus in vivo. Taken collectively, our data support the concept that Dectin-1 is one of the earliest recognition pathways involved in the host response to A. fumigatus. Therefore, our central hypothesis is that the Dectin-1 beta glucan receptor is required for immunity against A. fumigatus and successful host defense against invasive pulmonary aspergillosis. We plan to test our hypothesis with the following Specific Aims: (1) To test the hypothesis that Dectin-1 is required for innate and adaptive immune function against A. fumigatus and (2) To test the hypothesis that IL-1 is essential for immunity to A. fumigatus. The results of these studies will provide invaluable insight into first-line defense mechanisms against A. fumigatus and will hopefully lead us to develop novel immunotherapeutic strategies to augment host defense against A. fumigatus in susceptible individuals.