Pneumocystis carinii (PC) pneumonia is a significant problem in immunocompromised patients, particularly those with HIV. It has been well documented that the presence of CD4+ T cells is required for resolution PC infections. In addition, it has recently been reported that mice that are deficient in B cells are susceptible to PC (4,9). This is important because AIDS patients have been shown to have B cell defects that may also render them susceptible to PC. Until recently, there have not been good animal models for studying the role of B cells in host defense to infectious diseases. Although B cell deficient mice have proven to be useful, it is not possible to determine whether susceptibility to PC in these mice is due to a lack of natural antibody, PC-specific antibody, or B cell effector functions such as antigen presentation, costimulation of T cells, or cytokine production. The goal of this proposal is to test the hypothesis that B cells play multiple roles in the resolution of PC including activating CD4+ cells through antigen presentation, producing protective antibody, and producing cytokines that lead to resolution of PC pneumonia (PCP). We will utilize existing mice that are transgenic for the B cell receptor as well as generate new murine models including 1) making mixed chimeric mice whose B cells are defective in expression of cytokines or costimulatory molecules and 2) generating new transgenic mice whose B cells express the Herpes Simplex Virus thymidine kinase gene. These new mice will have B cells that are susceptible to killing by ganciclovir. With these murine models we will address the following specific aims: 1) to determine whether B cell-T cell interactions are required for resolution of PCP; 2) to determine whether B cell-produced cytokines are required for the resolution of PC; 3) to determine whether protection against PCP is dependent on specific recognition of PC antigens by the B cells; 4) to determine whether natural antibody is required for resolution of PCP; and 5) To determine the kinetic requirements for B cell function in PC infection. Understanding host defense to PC is critical for developing vaccines or efficient therapies for preventing this potentially fatal infection.
