Pneumocystis carinii (Pc) is a poorly understood but significant current health problem in immunocompromised individuals, including those with Acquired Immunodeficiency Syndrome. To gain more information concerning the basic biology and opportunities for intervention with this organism, this project will develop and exploit two new models of Pc infection in the mouse to study the immunological mechanisms and genetic determinants of variation in the mammalian response to Pc. The following three specific aims will be addressed. 1. Development of two new murine models of Pc infection. These are: a. The single gene mutation """"""""severe combined immunodeficiency"""""""" (gene symbol scid). Homozygotes for this mutation have essentially no antigen-specific immunity at any time in their lives, and develop and die from severe Pc infection. b. Irradiated normal recipients of bone marrow from mice bearing the """"""""lymphoproliferation"""""""" (symbol lpr) mutation. Unlike recipients of normal marrow, recipients of lpr marrow develop an apparent autoimmune syndrome that leads ultimately to profound cellular depletion of the lymphoid system, (presumed) severe immunodeficiency, and clinically evident Pc infection. 2. What are the important immunological mechanisms in resistance to and pathogenesis from Pc? The roles of a. B lymphocytes and antibodies, b. T lymphocytes, and c. non-antigen- specific accessory cells will be evaluated. 3. What are the genetic determinants of variation in the host's immunological and pathological responses to Pc? While exposing various animals to a common source of Pc, we will examine the effects of different alleles at a. the Major Histocompatibility complex (MHC), since this has major consequences for many forms of immunological reactivity, and b. non-MHC loci. (If such differences are found, the number and location of the non-MHC genes responsible will be sought.) The methodologies to be employed in these studies include histological and ultrastructural tissue examination at the light and electron microscopic levels, ELISA assays, cellular immunofluorescence and FACS analysis, tissue immunohistochemistry in vitro generation and in vivo utilization of monoclonal antibodies and T cell lines and clones, and classical genetic crosses using inbred and congenic mouse strains.
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