Department of Pharmacology, School of Medicine
Host-pathogen interactions in CNS infection: Resolving cellular and molecular mechanisms of invasion and BBB function during pathological conditions.
The Gelli Lab studies the pathogenesis of human fungal pathogens with a particular focus on fungi that disseminate to the central nervous system (CNS). Among the fungi we study is Cryptococcus neoformans - the leading cause of fungal meningoencephalitis in immunocompromised individuals. Our studies are aimed at resolving the molecular mechanisms mediating the interplay between fungi and the CNS. This interest was spearheaded in part by our study of the extracellular proteome of C. neoformans, where we identified a key fungal protease that promotes fungal disease in the CNS. Current studies include translation of our basic research to develop anti-virulence drugs and a platform technology that will deliver therapeutic drugs across the blood-brain barrier (BBB). Our efforts are also directed at understanding the host-pathogen interactions and in doing so, we have focused on key resident proteins of brain microvascular endothelial cells (i.e. BBB) that facilitate transcellular and/or paraceullar movement across the BBB.
Our current research efforts include collaborative studies aimed at resolving the pulmonary-to-CNS dissemination of Coccidioides, the cause of Valley Fever throughout the Southwestern United States, and a novel diagnostic tool that would differentiate a pulmonary cancer nodule from a fungal nodule.
Our interest in the BBB during pathological conditions has resulted in a collaborative study aimed at understanding how endothelial cell senescence during aging alters BBB function and how that impacts the onset of dementia and Alzheimer’s disease.
Grad Group Affiliations
- Biochemistry, Molecular, Cellular and Developmental Biology
- Molecular, Cellular and Integrative Physiology
- Pharmacology and Toxicology
- Molecular Cellular Biology & Physiology
- PTX 201 Principles of Pharmacology and Toxicology. PTX graduate group, Fall Quarter
- PHA 400 Principles of Pharmacology, First year medical students., Winter Quarter, Instructor and co-IOR
- PTX 203 Integrated physiological systems, cardiovascular, reproductive, immune and nervous system. PTX graduate group., Spring Quarter, Instructor and co-IOR
- MIB 201L MGG - Microbiology Laboratory Rotations, Fall and Winter Quarter
- BCB 215 - Spring Quarter
- Gelli - GBSF, Dept of Pharmacology, 3rd Floor Room 3409A http://pharmacology.ucdavis.edu/
- Graduate Students: Javier A. Garcia (BMCDB); Dylan M Lanser (MGG); Research Scientist: Dr. Kiem Vu; Undergraduate students: Mariela Duarte (Global Disease Biology, senior thesis project); Devi Jayakrishnan (Biomedical engineering, OEOES Summer Research Fellowship recipient);
Honors and Awards
- 1992 Graduate Scholar, Provincial Government of Ontario, Canada.
- 1993 Baily Scholar Award, University of Toronto, Canada
- 1998-2000 NSERC Post-doctoral 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
- 2019 Selected, 2020 Faculty Leadership Academy, UC Davis
- American Society of Microbiology
- American Society for Biochemistry and Molecular Biology
- Genetics Society of America
• Ph.D. University of Toronto, Canada
Aaron PA, & Gelli A. (2019) Harnessing the activity of the fungal metalloprotease, Mpr1, to promote crossing of nanocarriers through blood-brain barrier. ACS - Infectious Diseases (in press), Journal of the American Chemistry Society.
Vu K, Garcia JA, Gelli A. (2019) Cryptococcal meningitis and anti-virulence therapeutic strategies. Frontiers in Microbiology, The blood-brain barrier in infectious disease: Pathogenic mechanisms and therapeutic strategies. https://doi.org/10.3389/fmicb.2019.00353
Thompson GR III, Krois CR, Affolter VK, Everett AD, Varjonen EK, Sharon V, Singapuri A, Dennis M, McHardy I, Sik H, Fedor DM, Wiederhold NP, Aaron PA, Gelli A, Napoli JL, White SD. (2019) Fluconazole-induced alopecia: Examination in an animal model and human cohort. Antimicrobial Agents & Chemotherapy 63(2):e01384-18. https://aac.asm.org/content/aac/63/2/e01384-18.full.pdf
Na Pombejra S, Jamklang M, Uhrig JP, Vu K, Gelli A. (2018) The structure-function analysis of the Mpr1 metalloprotease determinants of activity during migration of fungal cells across the blood-brain barrier. PLOS ONE 13(8): e0203020. https://doi.org/10.1371/journal.pone.0203020
*Aaron, PA, Jamklang M, Uhrig, JP, Gelli A. (2018) The blood-brain barrier internalizes Cryptococcus neoformans via the EphA2-tyrosine kinase receptor. Cellular Microbiology, *Top Cited Article in Cellular Microbiology 2018-2019. 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. Fungal-specific metalloproteases and uses thereof. (2018) European Patent Office, Patent Granted on 2018-01-24, No.: EP2753358B1; United States Patent US 9,493,760 B2, Issued November 15th, 2016. https://patents.google.com/patent/EP2753358B1/en
∞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. ∞Editor's Choice
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. http://researchfeatures.com/2016/12/13/exploiting-fungal-mechanisms/
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 . *Editor's Pick
**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)
Gelli A, Higgins VJ & Blumwald E. (1997) The activation of plant plasma membrane Ca2+-permeable channels by race-specific fungal elicitors. Plant Physiol. 13:269-279 (PMID: 12223606).
Gelli A. & Blumwald, E. (1997) Hyperpolarization-activated Ca2+-permeable channels in the plasma membrane of tomato cells. J. Membrane Biol. 155:35-45 (PMID: 9002423).
Gelli * A., Aharon*GS, Snedden, W.A. & Blumwald, E. (1998) Activation of a plasma membrane Ca2+ channel by TGa1, a heterotrimeric G protein a-subunit homologue. FEBS Lett. 424:17-21 (*shared first authorship) (PMID: 9537507)
Gelli, A. & Blumwald, E. (1993). Calcium retrieval from vacuolar pools: Characterization of a vacuolar calcium channel. Plant Physiol. 102:1139-1146 (PMID: 12231891).
Pantoja O, Gelli A, & Blumwald, E. (1992) Voltage-dependent calcium channels in plant vacuoles. Science, 255:1567-1570 (PMID: 17820172).