C. neoformans causes a life-threatening meningoencephalitis in about 10% of patients with AIDS. The pathogenesis of cryptococcal infections is poorly understood. We propose to answer basic questions of C. neoformans pathogenesis using a rat model system. Over the past year Dr. Goldman has developed various rat models of cryptococcosis and these offfer significant advantages over existing animal systems. The time course of infection will be studied by characterizing the cellular, cytokine, and antibody responses. Cryptococcal meningoencephalitis will be established by infusion of C. neoformans into the rat cerebrospinal bluid. The host response in the brain will be studied including tghe cellular response and cytokine induction profile in the brain. A model of reactivation with immunosuppression will be developed to explore the pathogenesis of reactivation disease. Monoclonal antibodies (mAbs) to C. neoformans polysaccharide will be generated from rats. Rat mAbs will be characterizd serologically, molecularly, and by competition with pre-existing mouse mAbs. The rat mAbs will be used to study the pharmacokinetics of C. neoformans capsular glucuronoxylomannan (GXM) in the presence and absence of antibody. Although GXM is an established immunomodulator which accumulates in body tissues and contributes to virulence, relatively little is known about the fate of GXM in infection. The organ distribution and half-life of GXM will be studied using ELISA and radiolabelled antibody and GXM derivatives. mAbs will also be used to explore passive antibody protection in the rat and the potential of antibody to be used for imaging. Preliminary data indicates that radiolabelled antibody to GXM can be used to image an infection. Radiolabelled imaging offers a powerful tool for studying the pathogenesis of infection.
|He, Wu; Casadevall, Arturo; Lee, Sunhee C et al. (2003) Phagocytic activity and monocyte chemotactic protein expression by pulmonary macrophages in persistent pulmonary cryptococcosis. Infect Immun 71:930-6|
|Goldman, D L; Khine, H; Abadi, J et al. (2001) Serologic evidence for Cryptococcus neoformans infection in early childhood. Pediatrics 107:E66|
|Goldman, D L; Lee, S C; Mednick, A J et al. (2000) Persistent Cryptococcus neoformans pulmonary infection in the rat is associated with intracellular parasitism, decreased inducible nitric oxide synthase expression, and altered antibody responsiveness to cryptococcal polysaccharide. Infect Immun 68:832-8|
|Goldman, D L; Fries, B C; Franzot, S P et al. (1998) Phenotypic switching in the human pathogenic fungus Cryptococcus neoformans is associated with changes in virulence and pulmonary inflammatory response in rodents. Proc Natl Acad Sci U S A 95:14967-72|
|Goldman, D L; Casadevall, A; Zuckier, L S (1997) Pharmacokinetics and biodistribution of a monoclonal antibody to Cryptococcus neoformans capsular polysaccharide antigen in a rat model of cryptococcal meningitis: implications for passive immunotherapy. J Med Vet Mycol 35:271-8|
|Goldman, D L; Casadevall, A; Cho, Y et al. (1996) Cryptococcus neoformans meningitis in the rat. Lab Invest 75:759-70|
|Goldman, D; Cho, Y; Zhao, M et al. (1996) Expression of inducible nitric oxide synthase in rat pulmonary Cryptococcus neoformans granulomas. Am J Pathol 148:1275-82|