THE ROLE OF CXC CHEMOKINES IN INVASIVE ASPERGILLOSIS

侵袭性肺曲霉菌病是免疫抑制的常见和毁灭性并发症，并且在最佳可用治疗下具有大于85%的死亡率。 虽然对肺曲霉菌病中宿主的先天性免疫应答知之甚少，但动物和人体的体外和体内研究表明，中性粒细胞对于从肺中有效清除该微生物至关重要。 最近，CXC趋化因子家族的成员，包括巨噬细胞炎性蛋白-2（MIP-2）、KC和它们的人功能同源物、白细胞介素-8（IL-8）、Gro-α和Gro-β/γ，已显示在多种宿主炎性应答中，包括在肺部感染的情况下介导嗜中性粒细胞募集和活化。该建议的假设是，在侵袭性肺曲霉病中，中性粒细胞流入肺是由CXC趋化因子介导的，并且这些配体或其受体的操纵将显著影响感染的结果。建立侵袭性肺曲霉病小鼠模型，以评估以下特定目的：I）确定配体MIP-2和KC及其受体CXC趋化因子受体2（CXCR 2）在正常和免疫抑制小鼠中的表达的时间过程和幅度，所述小鼠用气管内烟曲霉攻击; II）确定配体MIP-2和KC对宿主防御A.通过评估用中和性抗MIP-2或抗KC抗体被动免疫的动物中的感染结果，确定受体CXCR 2对宿主防御A.通过评估以下动物中的感染结果来评估在烟曲霉中的感染：a）用中和性抗CXCR 2抗体被动免疫的动物，和B）CXCR 2敲除动物;和IV）评估配体MIP-2或KC在烟曲霉中的肺内转基因表达的作用。烟曲霉肺炎，通过检查以下动物中的感染结果：a）肺特异性MIP-2或KC转基因动物，和B）使用腺病毒基因治疗在肺中瞬时表达MIP-2或KC转基因的动物。 所描述的研究的性能将提供重要的见解CXC趋化因子作为介导的嗜中性粒细胞依赖性宿主防御肺曲霉病，这可能会导致识别新的疗法，用于治疗这种毁灭性的疾病的作用。

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.