THE ROLE OF CXC CHEMOKINES IN INVASIVE ASPERGILLOSIS

侵袭性肺曲霉菌病是免疫抑制的一种常见和破坏性的并发症，如果采用最佳的治疗方法，死亡率可达85%以上。虽然对肺曲霉菌病宿主的先天免疫反应知之甚少，但在动物和人类的体外和体内研究表明，中性粒细胞对于有效地将这种微生物从肺中清除是至关重要的。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及其人类功能同系物白介素8(IL-8)、Gro-α和Gro-β/γ，被证明在包括肺部感染在内的多种宿主炎症反应中介导中性粒细胞募集和激活。该方案的假设是侵袭性肺曲霉菌中性粒细胞进入肺内是由CXC趋化因子介导的，对这些配体或其受体的操作将显著影响感染的结局。建立了一种侵袭性肺曲霉菌病小鼠模型，以评估下列特定目标：1)测定MIP-2和KC及其受体CXC趋化因子受体2(CXCR2)在正常和免疫抑制小鼠气管内攻击后的表达时程和大小；2)通过评估中和抗MIP-2或抗KC抗体被动免疫动物的感染结局，确定MIP-2和KC在宿主防御中的作用；Iii)通过评估受体CXCR2在宿主防御烟曲霉菌中的作用，评估：a)中和抗CXCR2抗体被动免疫的动物和b)CXCR2基因敲除动物的感染结果；以及iv)通过检测肺特异的MIP-2或KC转基因动物的感染结果，评价MIP-2或KC配体在烟曲霉菌肺炎中肺内转基因表达的影响，以及b)使用腺病毒基因治疗在肺内瞬时表达MIP-2或KC转基因动物的感染结果。所描述的研究将为CXC趋化因子作为中性粒细胞依赖的宿主防御在肺曲霉菌病中的中介作用提供重要的见解，这可能导致识别可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.