Pulmonary infection with the fungal pathogen, P. carinii, is a common and often fatal complication of HIV infection. Previous work from our laboratory has shown that pulmonary recruitment of T-lymphocytes is critical for successful host defense against infection. Preliminary data in support of this application show that lymphocytes recruited into lung tissue in response to P. carinii express the CXCR3 chemokine receptor. Furthermore, mice deficient in CXCR3 have increased susceptibility to P. carinii infection. This proposal will investigate CXCR3-mediated lymphocyte recruitment in a murine model of P. carinii pneumonia. Experiments proposed will test the hypothesis that effective host defense against pulmonary infection with P. carinii requires local generation of CXCR3 ligands (MIG, IP-10, I-TAC) to recruit T-iymphocytes into lung tissue. We will examine pulmonary release of the three CXCR3 ligands: CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC) in response to infection and will test that concept that gene transfer of CXCR3 ligands can provide a novel form of immune enhancement during states of immunodeficiency. There are 3 Specific Aims: 1. To localize cellular sources of CXCR3 ligands in lung tissue at serial intervals after inoculation of P. carinii using flow cytometry and laser capture microdissection. 2. To demonstrate that CXCR3 is upregulated in memory T-lymphocytes recruited to lung tissue in response to P. carinii and that CXCR3+ T-lymphocytes enhance Th1 responses to infection. 3. To demonstrate that local delivery of CXCR3 ligands by gene transfer will enhance clearance of infection in normal mice and ameliorate infection in mice depleted of CD4+ T-lymphocytes. The results of these experiments will provide new information on how lymphocytes participate in host defense against P. carinii pneumonia and may lead to novel approaches to augment immune function in the HIV-infected host.
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