In this renewal/resubmission, this Program Project will continue to develop novel vaccine candidates and vaccination for HIV-related pulmonary pathogens. A concern of the prior submission was a lack of synergy between projects focused on Pneumocystis jirovecii (P. murina in mice) and Mycobacterium tuberculosis as the immunological mechanism needed to control these HIV-associated pathogens are very disparate. Vaccine induced protection against PCP relies largely on antibody responses whereas TB requires T-cells responses. To achieve greater focus and synergy on a significant, persistent pulmonary pathogen, we have chosen to focus this resubmission application solely on the fungal pathogen, Pneumocystis jirovecii (P. murina in mice). Although the lungs contain resident phagocytes with some activity against microbial pathogens, efficient host defense requires the capacity to rapidly expand the numbers and functions of immune effector cells in lung tissue in response to an infectious challenge. The lungs mount a cellular response to such a challenge mainly by delivering new cells to lung tissue from other cellular compartments (bone marrow, lymphoid tissue) through the vasculature. The overall theme of this Program Proiect is to develop vaccination approaches to enhance the delivery of immune effector cells into lung tissue in order to prevent colonization or augment clearance of Pneumocystis. We believe that efficient vaccines for respiratory pathogens must stimulate both cellular and antibody responses at the site of host exposure to the pathogen- at mucosal surfaces in lung tissue. Furthermore, to adequately address the global problem of respiratory infection associated with HIV infection, candidate vaccines should have efficacy both in normal hosts and in persons with diminished numbers or function of T-lymphocytes.
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