Although HAART treatment has successfully reduced morbidity and mortality from Pneumocystis jiroveci infection, there has been increasing concern about pulmonary complications from OIs in AIDS patients. However, how the two predominant immune variables in AIDS, CD4 function and type I IFN production, affect these complications, are not understood. We have found in preliminary studies that the immune response of mice to mouse Pneumocystis sp. (hereafter referred to as PC) is strongly polarized to a Th2-type response and that this polarization is CD4 T cell-dependent. Interestingly, in the absence of IFN-a receptor (IFNAR) signaling, the Th2 response was even more intense and these mice have type I hypersensitivity-like pathologic sequelae that do not resolve despite clearance of the PC and eventually results in severe fibrosis. Thus, in the absence of IFNAR signaling, PC infection initiates a fibrotic response that continues to develop even after PC can not be detected in the lungs. In addition, we found that B cell-deficient mice with PC pneumonia (PCP) have greater lung damage if they also have CD4 T cell function. Thus, we hypothesize that IFNAR signaling plays a critical role in modulating immune responses to PC and that pulmonary complications of PC infection are exacerbated by a deficiency of IFNAR signaling and/or reconstitution of CD4 T cell function. To address this hypothesis we propose to accomplish the following aims: l. to determine the role of IFNAR signaling in modulating the PC-driven Th2 host response; 2. to determine the role of IFNAR signaling in modulating PC-driven reconstitution disease; and 3. to determine the immunological mechanism by which IFNAR signaling modulates the host response to PC. The experiments proposed will establish how the presence or absence of IFNAR signaling and the presence or absence of CD4 T cell function determines how the host responds to PC infection. These results should lead to a better understanding of how the functional status of both CD4 T cells and IFNAR signaling in AIDS patients affect susceptibility to reconstitution disease or other inflammation-mediated pulmonary complications. ? ? ?
Showing the most recent 10 out of 24 publications
