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

Fungal pathogens are notorious for causing chronic and latent infections, b ut the mechanism by which they evade the immune response is poorly understo od. A major limitation in the study of chronic fungal infection has been th e lack of suitable animal models where the infection is controlled and yet persists. Pulmonary Cryptococcus neoformans infection in rats results in a diffuse pneumonitis that resolves without dissemination or scarring except for the persistence of interstitial and subpleural granulomas that harbor v iable cryptococci inside macrophages and epithelioid cells. Infected rats a re asymptomatic but remain infected for as long as 18 months after inoculat ion with C. neoformans, Containment of infection is associated with granulo ma formation that can be partially abrogated by glucocorticoid administrati on, Using this model, we identified several features associated with persis tent infection in the rat lung, including (i) localization of C, neoformans to discrete, well-organized granulomas; (ii) intracellular persistence of C, neoformans within macrophages and epithelioid cells; (iii) reduced induc ible nitric oxide synthase expression by granulomas harboring C. neoformans ; and (iv) reduced antibody responses to cryptococcal polysaccharide. The r esults show that maintenance of persistent infection is associated with dow nregulation of both cellular and humoral immune responses.