Protective determinants of antibodies to the fungal pathogen Cryptococcus neoformans
Nussbaum, Gabriel Jay
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This study focuses on the properties of antibodies to the pathogenic fungus Cryptococcus neoformans that allow them to modify the course of infection. C. neoformans is distinguished from other fungi by its large polysaccharide capsule which is a major determinant of its pathogenicity. I analyzed three parameters of the antibody response to the polysaccharide capsule: antibody idiotype, isotype, and epitope specificity. By using a specific anti-idiotypic reagent I have shown that the response is highly restricted to one idiotype in BALB/c mice but not in other mouse strains, both normal and autoimmune. The generation of idiotype negative antibodies and their characterization is currently being pursued.;Antibodies mediate protection through their Fc regions and different subclasses predominate in response to particular antigens. I have found that the IgG3 subclass, which predominates in response to thymus independent type 2 antigens such as cryptococcal polysaccharide, is not protective against C. neoformans. These IgG3 antibodies can block protection conferred by IgG1 and IgG2a antibodies through an unknown mechanism that depends solely on isotype. This finding raises the intriguing possibility that antibodies to C. neoformans that arise during infection, or are elicited by immunization could promote infection or contribute to disease susceptibility.;The comparison of two IgM Mabs, 12A1 and 13F1, revealed a role for epitope specificity in mediating protection. These Mabs derive from the same B cell precursor and differ by only several somatic mutations. Intraperitoneal administration of Mab 12A1 before lethal infection of A/J mice prolongs their survival significantly compared to controls, whereas Mab 13F1 has no effect. To further characterize epitope specificity and to develop a strategy to focus the immune response on eliciting protective antibodies, I screened a phage display library for peptides which bind our anti-polysaccharide Mabs and will serve as mimotopes of protective or non-protective epitopes. These can be used to direct and restrict the natural immune response to protective epitopes, and through linkage to appropriate carriers protective isotypes can be selected.;Infection and vaccination may elicit non-protective and protective antibodies, either of which may predominate and influence the outcome of a polyclonal response. The lack of effective measures to eradicate infection in the case of anti microbial resistance or in the setting of immunosuppression suggests that therapy with the most protective antibodies should be considered as a viable alternative.