Pulmonary immune response to Cryptococcus neoformans clinical isolates

Abstract

Cryptococcal meningitis, caused by the opportunistic fungal pathogen Cryptococcus neoformans, is a leading cause of HIV-related mortality worldwide, and a frequent cause of morbidity and mortality in other immunocompromised patient populations. In healthy individuals, exposure to C. neoformans in early childhood results in a latent pulmonary infection that is asymptomatic, but leads to the formation of lung granulomas. When the immune system fails, due to HIV or medical interventions that suppress immunity, immune control in the pulmonary granuloma is lost and the latent C. neoformans infection disseminates to cause meningitis. Treatment of cryptococcal meningitis requires appropriate antifungal therapy, management of intracranial pressure, and supportive care. In the case of HIV infection, antiretroviral therapy is initiated following successful resolution of cryptococcal meningitis. However, in a subset of individuals, the restoration of an intact immune system (i.e., via antiretroviral therapy), will trigger a dysregulated hyper-inflammatory response to C. neoformans antigen, known as immune reconstitution inflammatory syndrome (IRIS). The host immune cells and effector functions critical for controlling latency or promoting a dysregulated hyper-inflammatory response in IRIS have yet to be fully characterized. Currently, there are very few experimental mouse models for studying latent C. neoformans infection and cryptococcal IRIS. However, recent advances in the characterization and categorization of clinical isolates based on virulence phenotype and genetic background, allowed us to develop novel mouse models that recapitulate latency and certain aspects of cryptococcal IRIS. In this thesis, two such models are presented – a mouse inhalation model of latent C. neoformans infection and a mouse inhalation model of hypervirulent C. neoformans infection. Thus, the aims of this thesis are to 1) define and characterize novel mouse models of C. neoformans infection using clinical isolates, and 2) determine how the pulmonary immune response is able to control or become perturbed by the fungal pathogen.