Infection by optic pathogens such as Pneumocystis carinii (Pc) constitute the major fatal consequence of Human Immunodeficiency Virus HIV-induced Acquired Immunodeficiency Syndrome (AIDS). Since the number of disposed AIDS patients continues to increase worldwide, these opportunistic infections represent major and increasing public health challenges. The basic biology and genetics of the host-opportunistic pathogen interaction are not yet well understood, however. Moreover, restoration of immune function to an immunocompromised individual presents opportunities for either successful resolution of opportunistic infections or for inflammatory reactions themselves fatal to the host. With new drugs being developed to hold HIV and opportunistic infections temporarily at bay, and with hope of an eventual cure of HIV through molecular genetics, increasing numbers of patients will be faced with the challenge of reestablishing complete immune function and returning to normal life. This project will continue to utilize several genetically-defined mouse models to pursue the etiology, genetics, and therapy of Pc, via investigation of the following specific questions: 1) What are the effector mechanisms in pathogenesis from and immunity to Pc, and how can we provide protective or curative immunity with a minimum of harmful consequences? Previously developed cellular and humoral immunological reagents will be used to address these issues. 2) Which other microbial agents pathologically synergize with Pc, what are the mechanisms for such synergy, and how can we utilize the answers to these questions to choose the best targets and routes for therapy in cases of multiple infections? 3) What am the molecular and genetic determinants of Pc infectivity? Previously generated antibody and T cell reagents will be used to clone the gene and investigate the biology of the major antigenic protein of Pc, and to investigate the possible occurrence and relevance of Pc substrains. Standard genetic crosses will be used to reveal the genetic variables affecting host susceptibility to Pc.
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