This laboratory has two major areas of investigation: antibody function against opportunistic infections and mechanisms of fungal virulence. Their first goal is to develop antibody-based therapies and/or vaccines for opportunistic infections that plague patients with AIDS. Immunological therapies are needed for opportunistic infections because there is considerable evidence that microbicidal drugs are not sufficient to eradicate infection in individuals with severely impaired immune function. Two organisms are the focus of research: Cryptococcus neoformans and M. tuberculosis. C. neoformans causes a life-threatening and incurable meningoencephalitis in 5-6% of patients with late stage HIV infection. M. tuberculosis is an aggressive, devastating infection in patients with AIDS. For both C. neoformans and M. tuberculosis, protective antibodies have been generated. A monoclonal antibody to the C. neoformans capsular polysaccharide is in advanced pre-clinical development and is expected to enter Phase I testing shortly. Translation of bench observations to the bedside requires extensive studies in the basic immunology of antibody structure and function. For example, in collaboration with Scharff (see below), Casadevall is trying to understand the role of isotype and specificity in antibody protective efficacy. Site directed mutagenesis is being used to probe the molecular basis of specificity for antibodies which bind the C. neoformans capsular glucuronoxylomannan. Hence, a considerable effort is in place to understand the molecular and structural requirements for antibody efficacy in normal and immunocompromised hosts.

Apart from immunological studies, this laboratory is very interested in the pathogenesis of C. neoformans infection. Particular emphasis is being devoted towards attempting to understand how fungal virulence factors subvert host defense mechanisms. Melanin production by C. neoformans has been demonstrated to be an essential virulence factor. Melanin is made by a laccase enzyme using substrates from host tissues. In vitro studies suggest that melanin functions by scavenging oxidants made by host effector cells. Recently, the laboratory discovered the phenomenon of phenotypic switching by C. neoformans and established its association with virulence in rodents. Ongoing studies are directed towards elucidating the molecular mechanisms responsible for phenotypic switching and understanding how these function in virulence and pathogenesis.

Thus, trainees in the Casadevall laboratory have the opportunity to study aspects of humoral immunity and microbial pathogenesis.