MOLECULAR BIOLOGY OF PNEUMOCYSTIS CARINII

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Pneumocystis carinii is the most significant pulmonary pathogen in patients with the acquired immunodeficiency syndrome (AIDS). Despite substantial improvements in the diagnosis, treatment and prophylaxis of P. carinii pneumonia, it remains a leading cause of morbidity and mortality in AIDS. the causative agent was long considered to be a member of the Protozoa. Studies from this laboratory and others has demonstrated that P. carinii is in fact a member of the Fungi. Research into the biology and pathobiology of P. carinii has been hampered by the lack of an in vitro culture system. While antigens recognized in the normal immune response have been partially characterized in terms of molecular size and localization on intact P. carinii, the inability to maintain P. carinii in long-term culture has prevented the analysis of the role that these molecules play in vivo. The major surface antigen of P. carinii is the glycoprotein gp116 which shares several biochemical characteristics with fungal cell surface mannoproteins. The isolation of genomic and cDNA fragments encoding gp116 has been achieved and has shown gp116 to be a highly variable protein. The source and extent of this variability is not known and will be investigated using the polymerase chain reaction to amplify gp116 genes and cDNAs from single organisms. This allows an assessment of the variability and insight into the potential role of variability in evading the immune response. Another one of the goals of this proposal is to further characterize cloned gene fragments encoding the major surface antigens (gp116 and others) of P. carinii. The expression of these antigens in closely-related Fungi may help to elucidate the function of these molecules within P. carinii itself. by taking advantage of the close relationship of P. carinii to the yeasts, similar molecules in yeast will be isolated. The identification of these yeast homologs of P. carinii surface antigens will allow the detailed structural and functional analysis of these cell surface molecules. The detailed characterization of the structural and pathogenic roles of the P. carinii surface antigens will extend our understanding of the biology of this enigmatic organism and perhaps shed new light on strategies for the treatment and control of P. carinii pneumonia.