Pneumonia caused by the opportunistic pathogen Pneumocystis carinii is a primary cause of mortality in patients with acquired immunodeficiency syndrome, and in other immunocompromised hosts. The long range objective of the proposal is to determine the basis of acquired resistance to P. carinii infection, and to characterize the antigenic determinants of P. carinii recognized by the protective immune response at the molecular level. Of the antigens recognized by the immune response to P. carinii, passive immunization studies that have targeted an abundant surface molecule termed glycoprotein A (gpA) provide the only concrete examples of a specific P. carinii antigen important in protection against infection. The immediate goal of the proposal will be to characterize the molecular structure of gpA so that it may he more effectively targeted for immune attack against P. carinii. Mouse models of P. carinii pneumonia (PCP) provide the only experimental system in which immunization affords complete protection against infection. Since only mouse-derived P. carinii will establish infection in the mouse, immunological analysis of the pathogenesis of PCP mandates the use of mouse P. carinii antigens. Therefore, the first aim of the proposal will be to clone and characterize the cDNA encoding mouse P. carinii gpA, in order to deduce its primary amino acid structure and to provide a source of recombinant antigen for immunological analyses. Passive immunoprophylaxis with either of two monoclonal antibodies (MAbs) specific for gpA results in significant reduction in vivo of P. carinii organisms bearing their respective epitopes.
The second aim of the proposal will be to identify peptides recognized by these MAbs through the screening of combinatorial peptide display libraries. The ability of candidate peptides to function as protective immunogens will be compared to the protection afforded by passive immunization with their respective MAb. The candidate peptides will also be used to characterize the immune response to native gpA. Completion of the two objectives of this proposal will yield important molecular reagents to be used in the study of immunity to P. carinii, and will help define the molecular basis for acquired resistance to infection against PCP.
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