Fungi are an increasingly important cause of death and morbidity in both immunocompetent and immunocompromised patients. Cryptococcal meningitis caused by Cryptococcus neoformans is the most common cause of fungal central nervous system infection in the world. One million cases of Cryptococcal infection occur globally, largely in the context of AIDS and constitute one-third of all AIDS-associated deaths. Despite these public health threats, effective treatments for cryptococcosis are inadequate. Recent reports indicate a high importance of genome plasticity in the pathogenicity of C. neoformans. Aneuploidy formed de- novo during meiotic divisions adds to the diversity of cryptococcal population potentially generating new virulent strains. During pulmonary infection, cryptococcal cells become polyploids, which protects them from the host immune response. Changes in chromosomal copy number are responsible for the resistance to the azole drug fluconazole in vitro and in vivo. Despite mounting evidence that aneuploidy is crucial in pathogenicity of C. neoformans very little is known about the molecular mechanisms that govern changes in chromosomal copy number in this organism. The main objective of this proposal is to elucidate mechanisms responsible for generation of aneuploidy in C. neoformans with a particular emphasis on the connection between fluconazole treatment and aneuploidy. We will perform a detailed analysis of the effects of fluconazole on cell growth and nuclear division. In addition, we will elucidate basic architecture of the spindle assembly checkpoint (SAC) pathway in C. neoformans, and explore the possibility that the inhibition of this pathway is one of the causes of fluconazole-triggered aneuploidy leading to drug resistance. This work will contribute to our understanding of the mechanisms that are involved in chromosomal changes of a fungal pathogen during infection.
The proposed research aims at resolving an issue that is a significant concern in public health - drug resistance during infection of cryptococcal meningitis caused by Cryptococcus neoformans, which is the most common cause of fungal central nervous system infection in the world. C. neoformans becomes drug- resistant by changing gene copy number through unknown mechanisms. The main goal of this proposal is to uncover these mechanisms. Our studies will help to stop drug resistance in cryptococcosis and improve treatments of this devastating disease.
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