STRUCTURE AND EXPRESSION OF PNEUMOCYSTIS ANTIGEN GENES
Principal Investigator: James Stringer
Abstract: Pneumocystis pneumonia is a serious problem for AIDS patients and other immunocompromised individuals. This illness is caused by an unusual fungus (Pneumocystis jirovecii) that proliferates little when outside of a human being. Therefore, studies on the biology of Pneumocystis have relied principally upon P. carinii and P. murina, which inhabit rats and mice, respectively. Human Pneumocystis has at least one gene family (MSG) that has been implicated in antigenic variation in studies on P. carinii and P. murina. In this application, we propose structural and functional studies on gene families (MSG, PRT, MSR) in rodent Pneumocystis species. The overall goal of these studies is to determine if Pneumocystis gene families function to allow members of this genus to parasitize an immunocompetent host. Aim 1 will employ genomic data from P. carinii to determine where the proteins encoded by a gene family vary, and how this variability evolved. Deducing the mode of evolution will allow us to infer general function. Aim 2 will use genomic information to investigate expression of the P. carinii MSG family, a process that entails recombination at a unique expression site to cause a change in the sequence of the expressed gene. The bulk of the evidence suggests that gene conversion creates variation in the expressed copy of MSG. Aim 2 will examine this and other possibilities. Aim 3 will determine how often recombination occurs at the DCS locus of P. murina. These studies will both establish mice as a model for studying antigen variation in Pneumocystis, and set the stage for studies described in Aim 4, which will test the idea that the adaptive immune response can influence the degree of variation in MSG gene sequences residing at the expression site.
Funding Period: 1995-08-01 - 2010-03-31
more information: NIH RePORT
- Gene arrays at Pneumocystis carinii telomeresScott P Keely
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio 45267, USA
Genetics 170:1589-600. 2005..Long mononucleotide tracts were present in some MSR genes. These unstable sequences can be expected to suffer frequent frameshift mutations, providing P. carinii with another mechanism to generate antigen variation...
- Pneumocystis murina MSG gene family and the structure of the locus associated with its transcriptionScott P Keely
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
Fungal Genet Biol 44:905-19. 2007..carinii, but the block of conserved sequence in P. murina is nearly five times longer than in P. carinii, and much shorter than in P. wakefieldiae. These data indicate that the P. murina expression-site locus has a distinct structure...
- Common strategies for antigenic variation by bacterial, fungal and protozoan pathogensKirk W Deitsch
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021, USA
Nat Rev Microbiol 7:493-503. 2009....
- Complexity of the MSG gene family of Pneumocystis cariniiScott P Keely
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45220, USA
BMC Genomics 10:367. 2009..Several P. carinii MSG genes have been sequenced, which showed that genes in the family can encode distinct isoforms of MSG. The vast majority of family members have not been characterized at the sequence level...