STRUCTURE AND EXPRESSION OF PNEUMOCYSTIS ANTIGEN GENES

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DESCRIPTION: (Adapted from Applicant's Abstract). Pneumocystis carinii causes pneumonia in immunocompromised humans, and is a leading cause of morbidity among AIDS patients. P. carinii contains a gene family which encodes a large family of surface antigens named Major Surface Glycoprotein (MSG) in rat and human P. carinii, and gpA in P. carinii from ferrets. The complexity of the gene family endows P. carinii with the potential to present various structures on the surface of individual organisms, raising the suspicion that variation in MSG may function to help P. carinii escape the host immune system, and/or otherwise increase the capacity of the organism to survive in the mammalian lung. Recent results of monoclonal antibody studies in rats have shown that MSG expression varies in two ways: (i) not all organisms in a population express the same MSGs at the same time. (ii) certain MSG epitopes are abundant in some populations and undetectable in others. Despite the potential of P. carinii to adopt a variety of antigenic guises, immunity to this microbe is the norm, which encourages hopes for development of immunotherapy and vaccination procedures. In addition, MSGs are unlikely to function solely as antigens, and disruption of the production or fuction of MSGs may be therapeutic. Progress in these areas will require an understanding of the capacities of the organism to change its surface antigens, which will require understanding of the structure and expression of the family of MSG genes. An important clue to the mechanism of MSG variation has recently emerged. Most MSG mRNAs begin with the same leader sequence (LS), but this sequence is not present on 90% of the P. carinii chromosomes, all of which contain MSG genes. Analysis of genomic DNA fragments containing the LS showed that it is adjacent to at least 8 different MSG genes, and probably more. These data lead investigators to hypothesize that expressed MSG genes reside at a single site (LS), and that the MSG genes that are expressed in a given organism can be changed by recombination between MSG genes at the LS locus and one or more of the dozens of MSG genes located elsewhere in the genome. To test this hypothesis they propose the following specific aims... 1. Determine the structures of MSG loci. 2. Determine their role in antigenic variation. 3. Analyze the dynamics of MSG variation in the rat model.