THE ROLE OF CXC CHEMOKINES IN INVASIVE ASPERGILLOSIS

侵袭性肺曲霉病是免疫抑制的一种常见和破坏性并发症，在最佳可用治疗下死亡率超过85%。虽然对肺曲霉病的宿主先天免疫反应知之甚少，但动物和人体的体外和体内研究表明，中性粒细胞对于有效清除肺中的这种有机体至关重要。最近，CXC趋化因子家族的成员，包括巨噬细胞炎症蛋白-2 (MIP-2)， KC及其人类功能同源物，白细胞介素-8 (IL-8)， gro - α和gro - β / γ，已被证明在多种宿主炎症反应中介导中性粒细胞的募集和激活，包括在肺部感染的情况下。该建议的假设是，侵袭性肺曲霉病中中性粒细胞流入肺部是由CXC趋化因子介导的，对这些配体或其受体的操纵将显著影响感染的结果。建立了一种侵袭性肺曲霉病小鼠模型，以评估以下具体目的：1)确定在气管内烟曲霉攻击的正常和免疫抑制小鼠中，配体MIP-2和KC及其受体CXC趋化因子受体-2 （CXCR2）的表达时间和表达量；II)通过评估中和性抗MIP-2或抗KC抗体被动免疫动物的感染结果，确定配体MIP-2和KC对宿主防御烟熏假单胞菌的贡献；III)通过评估以下两种感染结果，确定受体CXCR2在宿主防御烟曲霉感染中的作用：a)中和性抗CXCR2抗体被动免疫动物和b) CXCR2敲除动物；IV)通过检测肺特异性MIP-2或KC转基因动物感染的结果，评估肺内MIP-2或KC转基因配体在烟曲霉菌肺炎中的表达效果：a)肺特异性MIP-2或KC转基因动物，b)使用腺病毒基因治疗在肺内短暂表达MIP-2或KC转基因动物。上述研究的表现将为CXC趋化因子在肺曲霉病中作为嗜中性粒细胞依赖性宿主防御介质的作用提供重要见解，这可能导致确定用于治疗这种毁灭性疾病的新疗法。

Invasive pulmonary aspergillosis is a common and devastating complication of immunosuppression, and carries a mortality of greater than 85 percent with optimal available therapy. While little is known regarding the host innate immune response in pulmonary aspergillosis, in vitro and in vivo studies in animals and humans suggest that neutrophils are critically important for effective clearance of this organism from the lung. Recently, members of the CXC chemokine family, including macrophage inflammatory protein-2 (MIP-2), KC and their human functional homologues, interleukin-8 (IL-8), Gro-alpha and Gro-beta/gamma, have been shown to mediate neutrophil recruitment and activation in a variety of host inflammatory responses, including in the setting of pulmonary infection. The hypothesis of this proposal is that the influx of neutrophils into the lung in invasive pulmonary aspergillosis is mediated by CXC chemokines, and that manipulation of these ligands or their receptor will significantly impact the outcome of infection. A murine model of invasive pulmonary aspergillosis has been developed to assess the following Specific Aims: I) to determine the time-course and magnitude of expression of the ligands MIP-2 and KC, and their receptor, CXC chemokine receptor-2 (CXCR2), in normal and immunosuppressed mice challenged with intratracheal Aspergillus fumigatus; II) to determine the contribution of the ligands MIP-2 and KC to host defense against A. fumigatus by evaluating the outcome of infection in animals passively immunized with neutralizing anti-MIP-2 or anti-KC antibodies; III) to establish the contribution of the receptor CXCR2 to host defense against A. fumigatus by evaluating the outcome of infection in: a) animals passively immunized with neutralizing anti-CXCR2 antibodies, and b) CXCR2 knock-out animals; and IV) to evaluate the effect o intrapulmonary transgenic expression of the ligands MIP-2 or KC in A. fumigatus pneumonia, by examining the outcome of infection in: a) lung-specific MIP-2 or KC transgenic animals, and b) animals transiently expressing the MIP-2 or KC transgene in the lungs using adenoviral gene therapy. The performance of the studies described will provide important insights into the role of CXC chemokines as mediators of neutrophil-dependent host defense in pulmonary aspergillosis, which may result in identification of novel therapies to be employed in the treatment of this devastating disease.