Dectin-1 and Invasive Pulmonary Aspergillosis

摘要：与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，特别是由烟曲霉引起的真菌感染。我们之前报道过β -葡聚糖受体Dectin-1识别的中断可以减弱肺泡巨噬细胞对烟曲霉的体外炎症反应。在这里，我们发现缺乏Dectin-1 （dectin -/-）的免疫能力小鼠天生对烟曲霉菌的气管内攻击敏感，在5天内表现出80%的死亡率，最终导致肺功能受损。攻击24小时后，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，随后烟曲霉菌肺生长不受控制。组织学评估进一步证明了Dectin-1-/小鼠烟曲霉嗜中性粒细胞募集缺陷和嗜中性粒细胞识别异常。体外研究表明烟曲霉不能诱导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烟曲霉。总的来说，这些结果支持Dectin-1在巨噬细胞来源的中性粒细胞募集信号的产生以及中性粒细胞介导的肺烟状芽孢杆菌的遏制中的基本作用。此外，我们在初步研究中进一步表明，IL-1和IL-1是体内抗烟曲霉先天免疫的重要介质。综上所述，我们的数据支持Dectin-1是参与宿主对烟螨反应的最早识别途径之一的概念。因此，我们的中心假设是Dectin-1 β葡聚糖受体是对烟曲霉的免疫和对侵袭性肺曲霉病的成功宿主防御所必需的。我们计划以以下具体目的来验证我们的假设：(1)验证Dectin-1是针对烟曲霉的先天和适应性免疫功能所必需的假设；(2)验证IL-1是对烟曲霉免疫所必需的假设。这些研究结果将为烟曲霉的一线防御机制提供宝贵的见解，并有望引导我们开发新的免疫治疗策略，以增强易感个体对烟曲霉的宿主防御。

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.