Department of Pharmacology, School of Medicine
My lab studies the pathogenesis of human fungal pathogens with a focus on Cryptococcus neoformans - the leading cause of fungal meningoencephalitis, a devastating brain infection. We are very interested in resolving the molecular mechanisms that facilitate the invasion of C. neoformans into the central nervous system. This interest was spearheaded in part by our study of the extracellular proteome of C. neoformans where we found that many of these secreted proteins are proteases and likely play a role in mediating fungal-host interactions. We have since developed an in vitro model of the blood-brain barrier and we have shown that it is a very useful system for defining the mechanisms of cryptococcal invasion into the CNS. In seeking to understand how C. neoformans crosses the blood-brain barrier, we recently discovered that it does so by means of a metalloprotease enzyme Mpr1, the presence of which we have also shown to be essential for establishing fungal disease in the central nervous system. The enzyme appears to selectively alter the surface of the blood-brain barrier by making it more permeable however the protein targets of this protease are unknown. Our aim is to characterize the molecular mechanisms of this key protease and screen for inhibitors.
We are also very interested in establishing whether this key protease can be coupled to nanocarriers in order to develop a brain-specific drug-delivery platform for the treatment of brain cancer.
We have also focused on the activation and regulation of a plasma membrane calcium channel in fungal cells and its potential use as a therapeutic target. Part of our NIH funded research program is currently focused on a high-throughput small molecule and off-patent drug screen to identify specific blockers of the channel and assess their therapeutic potential for the treatment of cryptococcal infection. We use a multidisciplinary approach that includes electrophysiology, imaging, cell biology, animal models, and molecular biology to validate the hits identified in our screen and test their ability to clear cryptococcal infections in vivo.
Grad Group Affiliations
- Biochemistry, Molecular, Cellular and Developmental Biology
- Pharmacology and Toxicology
- PTX 201 Principles of Pharmacology and Toxicology. PTX graduate group, Fall Quarter, Instructor
- PHA 400 Principles of Pharmacology, First year medical students., Winter, Instructor and co-IOR
- PTX 203 Integrated physiological systems, cardiovascular, reproductive, immune and nervous system. PTX graduate group., Spring Quarter, Instructor and IOR
- MIB 201L Microbiology Laboratory Rotations, MGG graduate students, Fall and Winter Quarter, Instructor
- BCB 215 - Spring 2018
- Gelli - GBSF, Dept of Pharmacology, 3rd Floor Room 3409A http://pharmacology.ucdavis.edu/
- Graduate Students: Phylicia A. Aaron (MGG); Javier A. Garcia (BMCDB). Postdoctoral Researcher: Dr. Kiem Vu
Honors and Awards
- 1992 Graduate Scholar, Provincial Government of Ontario, Canada.
- 1993 Baily Scholar Award, University of Toronto, Canada
- 1998-2000 NSERC PostDoctoral Scholar - Natural Science and Engineering Research Council of Canada
- 2006 Finalist, Burroughs Wellcome Scholar - Infectious Disease
- 2012 ID Week 2012TM Program Committee Choice Award (Infectious Diseases Society of America)
- 2013 Hartwell Investigator, The Hartwell Foundation
- 2014 Published article (MBio 2014) selected for Faculty1000Primne
- 2015 Elected, Councilor West for Medical Mycologists Society of the Americas (MMSA)
- 2017 Selected, Top Women-led technology companies, Sacramento, Fourth Wave
- American Society of Microbiology
- American Society for Biochemistry and Molecular Biology
• Ph.D. University of Toronto, Canada
Aaron, PA, Jamklang M, Uhrig, JP, Gelli A. (2018) The blood-brain barrier internalizes Cryptococcus neoformans via the EphA2-tyrosine kinase receptor. Cellular Microbiology (In press, http://onlinelibrary.wiley.com/doi/10.1111/cmi.12811/epdf)
Vu K, Thompson GR III, Roe CC, Sykes JE, Edreibe EM, Lockhart SR, Meyer W, Engelthaler DM, Gelli A. (2018). Flucytosine resistance in two Cryptococcus gattii clinical strains is indirectly mediated by the FCY2-FCY1-FUR1 pathway. Medical Mycology (in press, MM-2017-0159.R2). https://doi.org/10.1093/mmy/myx135
Gelli A. (2018) Editorial: A unique cytoskeleton-associated protein in Cryptococcus neoformans.
Virulence J, 13 March 2018 | https://doi.org/10.1080/21505594.2018.1451185
Na Pombjra S, M Salemi, Phinney BS, Gelli A. (2017). The metalloprotease, Mpr1, engages AnnexinA2 to promote the transcytosis of fungal cells across the blood-brain barrier. Front. Cell. Infect. Microbiol.
30 June 2017 | https://doi.org/10.3389/fcimb.2017.00296
Gelli A. Metalloproteases and uses thereof. United States Patent, Patent No., 9,493,760 B2, Date of Patent Issue: Nov. 15th, 2016.
∞Sykes J, Hodge G, Singapuri A, Yang ML, Gelli A, & Thompson GR III. (2016). In vivo development of fluconazole resistance in Cryptococcus gattii isolates from a cat. Medical Mycology 55, 396-401.
Yang ML, Uhrig JP, Vu K, Singapuri A, Dennis M, and Gelli A. and Thompson GR III. (2016). Fluconazole susceptibility in Cryptococcus gattii is dependent on the ATP binding cassette (ABC) transporter PDR11. Antimicrobial Agents & Chemotherapy 60(3):1202-1207 (PMID:26643330).
Gelli A. (2016). Exploiting fungal mechanisms to breach the blood-brain barrier. Research Features Magazine, Neuroscience 103:24-28.
Vu K, Bautos JM, and Gelli A. (2015). The Cch1-Mid1 high-affinity calcium channel contributes to the virulence of Cryptococcus neoformans by mitigating oxidative stress. Eukaryotic Cell 14(11):1135-1143 (PMID:26385891).
*Vu K, Tham R, Thompson GM, Bautos JM, Uhrig J, and Gelli A. (2014) Invasion of the central nervous system by Cryptococcus neoformans requires a secreted fungal metalloprotease. MBio 5(3) eo1101-14 (PMID:24895304).
*Selected for Faculty1000Prime
**Vu K, Eigenheer RA, Phinney BS, and Gelli A. (2013) Cryptococcus neoformans promotes its transmigration into the central nervous system by inducing molecular and cellular changes in brain endothelial cells. Infection & Immunity, 81(9):3139. DOI:10.1128/IAI.00554-13. Infection & Immunity, 81:3139-3147 (PMID:23774597).
**Featured in Spotlight: Selected as article of significant interest by the Editors.
Hong MP, Vu K, Bautos J, Tham R, Jamklang, M., Uhrig, J., and Gelli A. (2013) Activity of the fungal calcium channel pore, Cch1, is dependent on a modulatory region of Mid1. Eukaryotic Cell, 12:142-150 (PMID:23175710).
Hong MP, Vu K, Bautos J, and Gelli A. (2010) Cch1 restores intracellular Ca2+ in fungal cells during ER stress. J. of Biological Chemistry 285:10951-10958 (PMID: 20123986).
Vu, K., and Gelli A. (2010) *Fungicidal activity of fluconazole with astemizole and its analogues against Cryptococcus neoformans var. grubii and Cryptococcus gattii. Medical Mycology I-8
Vu K, Weksler B, Romero I, Couraud PO, Gelli A. (2009) An immortalized human brain endothelial cell line HCMEC/D3, as a model of the blood-brain barrier facilitates in vitro studies of CNS infection by Cryptococcus neoformans. Eukaryotic Cell 8:1803-1807 (PMID: 19767445).
Vu K, Bautos J, Hong MP and Gelli A. (2009) The functional expression of toxic genes: Lessons learned from molecular cloning of CCH1, a high-affinity calcium channel. Analytical Biochemistry 393:234-241 (PMID: 19580778)
Liu M, and Gelli A. (2008) Elongation factor 3, EF3, associates with the Ca2+ channel Cch1, and targets Cch1 to the plasma membrane of C. neoformans. Eukaryotic Cell 7:1118-1126 (PMID: 18503003)
Eigenheer, R.A., Lee, Y.J., Blumwald, E., Phinney, B. S., and Gelli, A. (2007) Extracellular GPI-anchored mannoproteins and proteases of Cryptococcus neoformans. FEMS Yeast Research 7: 499-510 (PMID: 17233760).
Liu, M., Du, P., Heinrich, G., Cox, G.M., and Gelli, A. (2006) Cch1 mediates calcium entry in Cryptococcus neoformans and is essential in low calcium environments. Eukaryotic Cell 5: 1788-1796 ( PMID: 16950930).
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: 752-771 (PMID: 15546358).
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. Virology 312:84-94 (PMID: 12890623).
Gelli A. (2002) Rst1 and Rst2 are required for the a/alpha diploid cell type in yeast. Molecular Microbiology 46:845-854 (PMID: 12410840)