This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project will test the hypothesis that deposition of Pneumocystis carinii in the respiratory tract stimulates release of IL-23 followed by downstream release of IFN and granulocyte/macrophage colony stimulating factor (GM-CSF) leading to clearance of infection. We will also test the concept that gene transfer of IL-23 can provide a novel form of immune enhancement during states of immunodeficiency. To test this hypostesis, the following specific aims will be performed:
In Specific Aim 1, we will localize cellular sources of IL-23 in lung tissue at serial intervals after inoculation of P. carinii.
In Specific Aim 2, we will demonstrate that neutralization of IL-23 using a soluble inhibitory RNA approach will compromise host defense against infection.
In Specific Aim 3, we will identify downstream inflammatory cytokines, specifically IFN and GM-CSF, in lung tissue in response to IL-23.
In Specific Aim 4, we will demonstrate that local delivery of IL-23 by gene transfer will enhance clearance of infection in normal mice and, in particular, ameliorate infection in mice depleted of CD4+ T-lymphocytes.
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