ResearchAngela Gelli
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Assistant Professor Ph.D., University of Toronto, 1997 Office Phone: (530) 754-6446 E-mail: acgelli@ucdavis.edu |
B.Sc., 1990 Chemistry - Biochemistry, University of Toronto, Canada
M.Sc., 1992 Electrophysiology, University of Toronto, Canada
Ph.D., 1997 Cell Biology / Electrophysiology, University of Toronto, Canada.
Research Interest:
Virulence determinants of fungal pathogenesis
We use a multidisciplinary approach to study human fungal pathogenesis and resolve the interplay between pathogen and host. Cryptococcus neoformans is an excellent model system to study fungal pathogenesis because it is an invasive opportunistic fungal pathogen that causes life-threatening infections in AIDS patients and individuals receiving immunosuppressive therapy. The primary route of entry into the body is the lung via the inhalation of fungal spores, and if not contained in the lung, C. neoformans enters the bloodstream and disseminates to bone, skin and the brain in particular. C. neoformans is the leading cause of fungal meningitis worldwide. In Southeast Asia and sub-Saharan Africa, where highly active antiretroviral therapy is less common, C. neoformans accounts for 45% of all cases of meningoencephalitis. Upon diagnosis, the mean survival time can be as short as four days and the mortality from HIV-associated cryptococcal meningoencephalitis is 13 to 44%. Although cryptococcal meningoencephalitis is recognized as an AIDS-related infection, C. neoformans is capable of causing disease in healthy, immunocompetent individuals. In order to cause meningoencephalitis, the fungal cells must survive in the bloodstream and cross the blood brain barrier (BBB). The mechanisms by which this occurs are just beginning to be elucidated but the key proteins on the surface of the pathogen that mediate the attachment to and the crossing of the BBB remain undefined. Understanding how C. neoformans invades the central nervous system is one of our research interests.
The second research project in the lab aims to resolve the role of calcium channel (Cch1-Mid1) in promoting growth of C. neoformans in host conditions. Far less is known about the function of the Cch1-Mid1 calcium channel complex in C. neoformans and about its role in promoting virulence. Given the primary functions of Ca2+-calcineurin-mediated signaling in controlling some key traits of C. neoformans that promote its survival during the infection process, the role of Cch1 within this signaling network is particularly interesting. We have identified a primary role for Cch1 in mediating calcium uptake in C. neoformans and promoting its survival in a low calcium environment, similar to conditions that C. neoformans would face during intracellular growth within macrophages. Macrophages may represent a low calcium environment where survival of C. neoformans may depend of Cch1 activity. Indeed survival of H. capsulatum within macrophages was reported to be calcium-dependent. Blocking Cch1 activity should presumably prevent the survival of C. neoformans within macrophages. However, due to the rapid and transient nature of the rise in free [Ca2+] cytosol in signaling cells, the window of susceptibility may be relatively small. Nevertheless, where Cch1 can be targeted for antifungal drug development will depend on the synthesis of pharmacological agents that could selectively block Cch1 with high affinity. Our findings also raise the possibility that the gating of the Cch1 channel may be controlled by mechanism other than voltage.
Selected Publications
Pantoaja O., Gelli A., Blumwald, E. (1992) Voltage-dependent calcium channels in plant vacuoles. Science, 255, 1567-1570. Abstract.
Pantoja, O., Gelli, A., Blumwald, E. (1992). Characterization of vacuolar Malate and Potassium channels under physiological conditions. Plant Physiol. 100, 1137-1141. Abstract.
Gelli, A. & Blumwald, E. (1993). Calcium retrieval from vacuolar pools. Characerization of a vacuolar calcium challen. Plant Physiol. 102,1139-1146. Abstract.
Plant P., Gelli, A., Blumwald E. (1994) Vacuolar chloride regulation of an anion selective tonoplast channel. J. Membrane Biol. 140, 1-12. Abstract.
Gelli, A., Higgins, V.J. & Blumwald, E. (1997). Activation of plant plasma membrane CA2+-permeable channels by race-specific fungal elicitors. Plant Physiol. 13, 269-279. Abstract.
Gelli, A. & Blumwald, E. (1997). Hyperpolarization-activated Ca2+ - permeable channels in the plasma membrane of tomato cells. J. Membrane Biol. 155,35 45. Abstract.
Blumwald E., Gelli A. (1997) Secondary inorganic ion transport in plant vacuoles. Adv. Bot. Res. 25, 401-417.
Gelli A., Aharon, G.S., Snedden W.A., Blumwald E. (1998) Activation of plasma membrane Ca2+ channel by TGalpha1, a heterotrimeric G protein alpha-subunit homologue. Abstract.
Higgins V.J., Lu H., Xing T., Gelli A., Blumwald E. (1999). The gene for gene concept and beyond: Interactions and SIgnals, Can. J. Plant Pathol. 20, 150-157. Abstract.
Gelli, A. (2002). Rst1 and Rst2 are required for the a/_ diploid cell type in yeast. Mol Microbiol 46:845-854. Abstract.
George, M.D., Samarkan, S., E. Reay, Gelli, A., Dandekar, S. (2003). High throughput gene expression profiling indicates loss of intestinal growth factors and cell cycle mediators during primary simian immunodeficiency virus infection. J Virol 312:84-94. Abstract.
Sottosanto, J., Gelli, A. and Blumwald E. (2004). DNA array analyses of Arabidopsis thaliana lacking a vacuolar Na+/H+ antiporter: Impact of AtNHX1 on gene expression. Plant Journal 5, 751-771. Abstract.
Liu M., Du P., Heinrich G., Cox G.M., Gelli A. (2006). Cch1 mediates calcium entry in Cryptococcus neoformans and is essential in low calcium environments. Eukaryotic Cell. Abstract.
Eigenheer, R. A., Lee, Y. J., Blumwald, E., Phinney, B. S., and Gelli A. (2007) Extracellualr GPI-anchored mannoproteins and proteases of Cryptococcus neoformans. (In press, FEMS Yeast Res, published online 19-Jan-2007).