Virulence determinants of fungal pathogenesis
Cryptococcus neoformans is a human fungal pathogen that causes an invasive and life-threatening infection primarily in patients with a compromised immune system. Once cryptococcal cells disseminate into the bloodstream, they cross the blood-brain barrier (composed of the brain endothelium) and cause meningoencephalitis, an often-deadly infection. C. neoformans is now the leading cause of fungal meningitis world-wide and accounts for a significant proportion of AIDS-related infections. How cryptococcal cells manage to breach the blood-brain barrier and enter the brain is not fully understood. Through the use of proteomics, molecular biology and an in vitro model of the blood-brain barrier, we are identifying and examining the role of several key surface proteins of Cryptococcus in breaching the barrier and promoting brain invasion. Since we believe that the relationship between cryptococcal cells and the brain endothelium is highly dynamic we are identifying the temporal protein expression profiles of the brain endothelium in response to C. neoformans. We anticipate that these studies will lead to an understanding of the mechanisms that promote the invasion of cryptococcal cells into the CNS, which we can then manipulate and exploit for the delivery of drugs into the brain to treat brain cancers and neurodegenerative diseases. In addition, the identification of key proteins (either on the pathogen or the brain endothelium) that facilitate CNS invasion may lead the way to the development of drugs that prevent fungal meningitis.
Treating a cryptococcal infection in an immunosuppressed individual is challenging in part because some of the best antifungal drugs (like azoles) are not fungicidal. We have characterized a calcium channel (Cch1-Mid1) in the plasma membrane of Cryptococcus neoformans that appears to be a promising target for the development of small molecules that could be used in combination to promote fungicidal activity of azoles. We are performing a high-throughput screen to identify molecules that target the channel and we expect to identify several new molecules that will have clinical relevance. We have also used a multidisciplinary approach (electrophysiology, molecular biology and cell biology) to characterize the role of this calcium channel in the pathogen. We found that cryptococcal cells require this channel when trying to survive in environments that are low in calcium such as macrophages. We have also performed the first mechanistic study of this calcium channel and found that it functions as a store-operated calcium selective channel that is essential for the survival of cryptococcal cells during ER (endoplasmic reticulum) stress. The ability of the channel to get to the plasma membrane where its function is required is dependent on a secondary protein, elongation factor 3. This protein has been of interest for a long time because it is an essential protein and it does not have a human homologue making it the perfect antifungal drug target. We are currently exploring how and when the two proteins associate and resolving the molecular mechanism of their interaction.
Ph.D., Cell Biology/Electrophysiology, University of Toronto, Ontario, 1997
B.Sc., Chemistry-Biochemistry, University of Toronto, Ontario, 1990
M.Sc., Electrophysiology, University of Toronto, Ontario, 1992
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, 1997-2000
Honors and Awards
Post-Doctoral Scholar, Natural Science and Engineering Research Council of Canada (NSERC), 1997
Select Recent Publications
Eigenheer RA, Lee YJ, Blumwald E, Phinney BS, Gelli A. Extracellular GPI-anchored mannoproteins and proteases of cryptococcus neoformans. (FEMS Yeast Res, published online 19-Jan-2007).
Liu M, Du P, Heinrich G, Cox GM, Gelli A. Cch1 mediates calcium entry in cryptococcus neoformans and is essential in low-calcium environments. Eukaryot Cell, 5:1788-1796, 2006.
George MD, Samarkan S, Reay E, Gelli A, Dandekar S. High-throughput gene expression profiling indicates loss of intestinal growth factors and cell-cycle mediators during primary simian immunodeficiency virus infection. Virol, 312:84-94, 2003.
Gelli A. Rst1 and Rst2 are required for the a/alpha diploid cell-type in yeast. Mol Microbiol, 46:845-854, 2002.