Cryptococcus neoformans is a fungal pathogen that causes meningoencephalitis in 6-8 percent of patients with AIDS. Infection is acquired by the inhalation of aerosolized yeast from the environment. Several lines of evidence suggest that cryptococcal meningoencephalitis results from the reactivation of a persistent pulmonary infection similar to infections caused H. capsulatum and M. tuberculosis. Nevertheless, the most commonly studied animal models of pulmonary cryptococcosis involve acute infection in susceptible mice and hence are inadequate to study the pathogenesis of persistent, pulmonary C. neoformans infections. We have recently characterized a rat model of pulmonary cryptococcosis that shares many of the clinical, pathological and serological findings of C. neoformans pulmonary infection in immunocompetent humans. This model provides a new tool to study the immunologic basis of C. neoformans persistence in tissue. The focus of this application is to study the basis of C. neoformans persistence as it relates to macrophage function. Macrophages play a central role as effectors and regulators of the rat and human inflammatory response to pulmonary cryptococcosis. In the first specific aim, we will test the hypothesis that the functional activation of macrophages correlates with the ability of the rat to control cryptococcal infection such that persistent infection in the lung is the result of macrophage down-modulation. In the second specific aim, we will investigate the basis for down-modulation of macrophage function. Hypotheses to be tested include that the changes in T-cell or macrophage derived cytokines are responsible for the decreased macrophage function associated with persistence. We will also examine the hypothesis that accumulation of cryptococcal polysaccharide within macrophages during infection directly inhibits macrophage function. In the third specific aim, we will develop immunologic strategies to enhance macrophage function which will eradicate C. neoformans persistence and thereby prevent the possibility of reactivation. Specific strategies to be employed include the administration of cytokines and a monoclonal antibody against the cryptococcal polysaccharide.
