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.
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