Gustavo Arrizabalaga, PhD
Professor of Pharmacology and Toxicology
and of Microbiology and Immunology
My lab focuses on elucidating the cell signaling mechanisms of growth and host pathogen interaction in the intracellular protozoan parasite Toxoplasma gondii.
Post-doctoral Fellow | Stanford University School of Medicine | Advisor: Dr. John Boothroyd
PhD | Massachusetts Institute of Technology, Cambridge, MA | Advisor: Dr. Ruth Lehmann
B.S. | Chemistry with Biology concentration | Haverford College, Haverford PA | Advisor: Dr. Julio De Paula
Honors and Awards
Chair Elect Division AA, American Society for Microbiology
Excellence in Teaching Award | WWAMI Medical Program | University of Idaho
Commitment to Diversity Faculty Award | WWAMI Medical Program | University of Idaho
Excellence in Teaching Award | WWAMI Medical Program | University of Idaho
R.M. Wade Teaching Excellence Award | University of Idaho
2008 - present
Member, Grant review panel | American Heart Association
Our main interest is the cellular and molecular biology of the protozoan parasite Toxoplasma gondii. Toxoplasma is an obligate intracellular parasite capable of infecting virtually any nucleated cell from a wide range of mammalian and avian species. Toxoplasma is one of the most widespread and successful protozoan parasites, and it is thought to infect a third of the world's population.
In immunocompromised individuals such as those with AIDS, leukemia, and lymphoma, and in immunosuppressed transplant recipients, new infections or reactivation of encysted parasites can lead to toxoplasmic encephalitis. Additionally, in congenital infections, the disease can lead to severe neurological problems or even death of a developing fetus. While there are drugs available to treat the acute stage of the parasite, these are often toxic to the patient and are not effective against the chronic stage of the infection. Thus, there is a need to discover new targets for treatment.
Central to the propagation of Toxoplasma within an infected individual as well as to the ensuing pathogenesis is the completion of its lytic cycle, which consists of attachment to a host cell, active invasion, intracellular replication and egress. This cycle depends on the
coordinated regulation of the parasite’s motility machinery, physiology, and secretory apparatus as well as on the ability of the parasite to adapt to environmental and physiological changes. My past research focuses on the signaling events and parasite proteins involved in the process by which the parasite exits its host cell [9-12]. Moreover, following up on observations that ionic homeostasis influences Toxoplasma egress, I have studied the role of ion channels and exchangers in the lytic cycle and stress tolerance of the parasite [9, 13]. Based on my program’s discoveries and observations I have focused my work on two interrelated questions: How does the parasite react and adapt to ion concentration changes, including those induced by anti-parasitic drugs? And how does the parasite regulate its motility as it moves from the inside of a cell to the extracellular environment? To tackle these questions my research program utilizes a multidisciplinary approach, which combines molecular genetics, cell and molecular biology, and physiology.
Current work in my research group focuses on:
1. Identifying and characterizing the proteins involved in egress and initiation of motility. Using a series of genetic screens and selections we have discovered that a Calcium Dependent Protein Kinase (CDPK), TgCDPK3 is needed for the parasite to respond to the calcium signals that induce the parasite to rapidly exit its host cell. In addition, using an animal model of Toxoplasmosis we have determined that Tgcdpk3 mutant parasites have decreased virulence.
Members of the CDPK family of kinases are of special interest as they are only present in plants and apicomplexan parasites and are absent in mammalian cells. Thus, CDPKs are being focused on as potential drug targets. We are currently identifying the
targets of TgCDPK3 as well as determining the particular steps during in vivo propagation that require this kinase.
2. Determining mechanisms of drug resistance in Toxoplasma gondii. Work on the parasite’s response to ion fluxes and other related stresses led us to the discovery of an inducible death pathway, which is dependent on a DNA damage response protein. We have recently discovered that disruption of TgMSH-1, a MutS homolog (MSH) in T. gondii, confers resistance to various anti-parasitic drugs including the ionophores monensin and salinomycin and the anti-malarial atovaquone. MSHs are critical components of the eukaryotic DNA mismatch repair machinery and can signal cell cycle arrest and apoptosis in response to DNA damaging agents. Accordingly, mammalian cells lacking certain MSHs are resistant to chemotherapeutic drugs, since the signaling of cell cycle arrest is disrupted. Similarly, we have observed that monensin causes gene expression changes and disruption of the cell cycle in T. gondii in a TgMHS1-dependent manner. Thus, by studying the adaptation of the parasite to the ionic stress caused by monensin, we have identified a novel protein in T. gondii that plays a role in an inducible death mechanism.
Interestingly, unlike previously described MSHs involved in signaling, which localize to the nucleus, TgMSH-1 localizes to the parasite mitochondrion. Our working model predicts that certain drugs affect the mitochondrion of the parasite directly or indirectly. This effect results in the activation of a signaling pathway, which includes
TgMSH-1 and results in parasite death. Our current focus is on identifying the particular stress that induces the TgMSH-1 dependent death as well as the signaling partners of this novel protein.
- Varberg, J.M., Padgett, L.R., Arrizabalaga, G., Sullivan, W.J., 2015. TgATAT-mediated α-tubulin acetylation is required for division of the protozoan parasite Toxoplasma gondii. mSphere
- Gaji, R. Johnson, D., Wang, M., Hudmon, A., and Arrizabalaga, G., 2015. Phosphorylation of a Myosin motor by TgCDPK3 facilitates rapid initiation of motility during Toxoplasma gondii egress. PLoS Pathog. 1(11):e1005268. PMID: 26544049
- Benmerzouga, I., Checkley, L., Ferdig, M., Arrizabalaga, G., Wek, R., and Sullivan, W., 2015. Guanabenz repurposed as an anti-parasitic with activity against acute and latent toxoplasmosis, Antimicrob Agents Chemother, 59(11):6939-45. PMID: 26303803
- Treeck, M., Sanders, J., Gaji, R., LaFavers, K., Child, M., Arrizabalaga, G., Elias, J., Boothroyd, J., 2014. A novel role of Calcium-dependent Kinase 3 in regulating metabolism in Toxoplasma gondii in addition to ionophore induced egress. PLoS Pathogen, 10(6):e1004197. PMID: 24945436
- Gaji, R., Checkley, L., Reese, M., Ferdig, M.T., and Arrizabalaga, G., 2014. Expression of the essential kinase PfCDPK1 from Plasmodium falciparum in Toxoplasma gondii facilitates the discovery of novel antimalarial drugs. Antimicrob Agents Chemother, 58(5):2598-607. PMID: 24550330
- Garrison, E., Treeck, M., Ehret, M., Garbuz, T., Oswald, B.P., Settles, M., Boothroyd, J., Arrizabalaga, G. 2012, A forward genetic screen reveals calcium-dependent kinase 3 is critical for calcium-induced egress in Toxoplasma. Plos Pathogen, 8(11): e1003049
- Lavine, M.D. and Arrizabalaga, G. 2012, Analysis of Monensin Sensitivity in Toxoplasma gondii reveals autophagy as a mechanism for drug induced death. Plos One, 7(7):e42107. PMID: 22848721
- Francia, M.E., Wicher S., Pace D.A., Sullivan, J., Moreno, S.N.J., and Arrizabalaga, G. 2011. A Toxoplasma protein with homology to intracellular type Sodium Hydrogen Exchangers is required for osmotolerance and protein processing. Experimental Cell Research. 317(10):1382-96
- Lavine, M.D. and Arrizabalaga, G. 2011. The antibiotic monensin causes cell cycle disruption of Toxoplasma gondii, mediated through the DNA repair enzyme TgMSH-1. Antimicrob Agents Chemother, 55(2): 745-55
- Garrison, E. and Arrizabalaga, G., 2009. Disruption of a mitochondrial homolog of a MutS DNA Repair Enzyme confers drug resistance in the pathogenic parasite Toxoplasma gondii. Molecular Microbiology, 72(2):425-41
- Saeij, J., Arrizabalaga, G. and Boothroyd J.C., 2008. A cluster of four surface antigen genes specifically expressed in bradyzoites, SAG2CDXY, plays an important role in Toxoplasma gondii persistence. Immunity and infection, 76(6):2402-10
- Lavine, M and Arrizabalaga, G., 2008 Exit from host cells by the pathogenic parasite Toxoplasma gondii does not require motility. Eukaryotic Cell, 7(1): 131-40
- Lavine, M.D., Knoll, L.J., Rooney, P.J. and Arrizabalaga, G. 2007. A Toxoplasma gondii mutant defective in responding to calcium fluxes shows reduced in vivo pathogenicity. Molecular and Biochemical Parasitology, Molecular and Biochemical Parasitology, 155(2): 113-122
- Fruth, I.A. and Arrizabalaga G., 2007. Toxoplasma gondii: Induction of egress by the potassium ionophore nigericin. International Journal of Parasitology, 37(14): 1559-67
- Lavine, M.D., and Arrizabalaga, G., 2007. Invasion and egress by the obligate intracellular parasite Toxoplasma gondii: potential targets for the development of new antiparasitic drugs. Current Pharmaceutical Design 13; 641-651.