Characterization of the antibody response to Cryptococcus neoformans

Abstract

The goal of this thesis was to characterize the antibody repertoire constituents that are used in the human antibody response to the capsular polysaccharide of the pathogenic yeast Cryptococcus neoformans, an opportunistic fungus that is ubiquitous in the environment. Although infections with C. neoformans do occur in normal hosts, such infections are rare compared to the markedly increased prevalence of cryptococcal meningoencephalitis in immunocompromised individuals, particularly those with the acquired immunodeficiency syndrome (AIDS), or patients who have undergone organ transplantation or steroid therapy. The central virulence factor of C. neoformans is its capsular polysaccharide, which is predominantly comprised of glucuronoxylomannan (GXM). GXM exerts a variety of deleterious effects on host immunity, and it has now been shown by several different groups that antibodies to GXM can enhance host immunity to C. neoformans infection in animal models. However, the role that antibodies to GXM play in natural resistance to infection in humans remains unknown. We and other groups have shown that both immunodeficiency virus (HIV)-uninfected and HIV-infected persons have antibodies to GXM in their serum. Although these data suggest that the quantity of antibody to GXM alone does not influence immunity to C. neoformans , our group has described qualitative differences in the antibody repertoire and specificity of antibodies to GXM between HIV-uninfected and HIV-infected individuals. These observations are consistent with the concept that qualitative antibody characteristics might influence resistance and susceptibility to C. neoformans. This thesis presents data revealing qualitative characteristics of human antibodies to GXM. The first chapter illustrates that human antibodies to GXM are derived from certain restricted B cell subsets and that the idiotypic characteristics of these antibodies are shared with a protective human monoclonal antibody to GXM. The second chapter provides evidence that the serum antibody repertoires of HIV-uninfected and HIV-infected individuals differ with respect to expression of certain antibody subsets, and that there was decreased expression of a certain antibody idiotype in HIV-infected patients who subsequently developed C. neoformans infection. The third chapter demonstrates that vaccination with a peptide mimic of the GXM epitope recognized by the protective human monoclonal antibody studied in chapter 1 induced an antibody response to GXM and protective immunity against C. neoformans infection in mice. Taken together, the data presented in this thesis support the concept that a protective antibody with certain defined characteristics can be used to identify surrogates for unknown polysaccharide epitopes that can elicit a protective immune response to C. neoformans.