Key to discovering novel and effective targets for drug development is the expansion of our understanding of processes that are specific and essential to the parasite. It is within this context that I have focused the last 15 years of my research career in elucidating the signaling and cellular processes involved in the propagation of the parasite through an infected tissue. Overall, my research program has been driven by the following general questions: what are the cues and proteins regulating how the parasite exits its host cell, and how is this parasite able to adapt to the variety of physiological environments and stresses it encounters during its life cycle? The two overarching projects in the lab are: 1) identifying and characterizing the proteins regulating egress, and 2) dissecting a signaling pathway that leads to parasite death in response to a variety of stresses, including drug treatment.
The Arrizabalaga Lab
Active egress from the host cell is a lytic process that requires parasite motility and calcium signaling. Using forward genetic approaches our lab has been investigating how Toxoplasma egress is regulated for the last fifteen years. Most recently we discovered that a calcium dependent protein kinase, TgCDPK3, is required for rapid egress in response to calcium fluxes. We have determined that besides egress, TgCDPK3 regulates calcium homeostasis, establishment of the chronic stage in vivo and parasite motility. Current projects involve identifying substrates of this unique kinase and determining its role during in vivo infection.
Parasite egress depends on calcium fluxes and signaling in both the parasite and the host cell. How the signals within the parasite and the host are integrated is not known. Toxoplasma replicates within a membrane bound vacuole called the parasitophorous vacuole (PV). We propose that proteins in the PV are key to the relay and integration of information between host and parasite. Accordingly, we have identified several calcium binding proteins that localize to the PV. Furthermore, we have identified a new PV protein that when disrupted affects several calcium dependent parasite functions. Current projects involve determining the role of those proteins during the lytic cylce and identifying the proteins that they interact with.
During its complex life cycle, Toxoplasma is exposed to a diversity of physiological environments. Consequently, this parasite must possess signaling molecules and mechanisms that would allow it to quickly adapt to a variety of stressors and environments. In addition, we hypothesize that in certain situations under which adaptation is not possible, the parasite will induce events that lead to its death. Consistent with this idea, we discovered a drug-induced signaling pathway that leads to parasite death and depends on a mitochondrial DNA damage repair enzyme and autophagy related events. Current projects include disecting the function of TgMSH1, the regulation of autophagy and the regulation of mitochondrial homeostasis