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Author: Donna Huber

Fall 2020 Newsletter

Learn about our research activities, faculty honors, new grants, and trainees from the summer and fall.

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Different Sensitivity of Control and MICU1- and MICU2-Ablated Trypanosoma cruzi Mitochondrial Calcium Uniporter Complex to Ruthenium-Based Inhibitors

The mitochondrial Ca2+ uptake in trypanosomatids shares biochemical characteristics with that of animals. However, the composition of the mitochondrial Ca2+ uniporter complex (MCUC) in these parasites is quite peculiar, suggesting lineage-specific adaptations. In this work, we compared the inhibitory activity of ruthenium red (RuRed) and Ru360, the most commonly used MCUC inhibitors, with that of the recently described inhibitor Ru265, on Trypanosoma cruzi, the agent of Chagas disease. Ru265 was more potent than Ru360 and RuRed in inhibiting mitochondrial Ca2+ transport in permeabilized cells. When dose-response effects were investigated, an increase in sensitivity for Ru360 and Ru265 was observed in TcMICU1-KO and TcMICU2-KO cells as compared with control cells. In the presence of RuRed, a significant increase in sensitivity was observed only in TcMICU2-KO cells. However, application of Ru265 to intact cells did not affect growth and respiration of epimastigotes, mitochondrial Ca2+ uptake in Rhod-2-labeled intact cells, or attachment to host cells and infection by trypomastigotes, suggesting a low permeability for this compound in trypanosomes.

Mayara S Bertolini, Roberto Docampo. Int J Mol Sci. 2020 Dec 7;21(23):E9316. doi: 10.3390/ijms21239316.

Rick Tarleton elected AAAS Fellow

Photo credit: Andrew Tucker

University of Georgia researcher Rick Tarleton has been elected as a 2020 American Association for the Advancement of Science (AAAS) Fellow by the AAAS Council “for distinguished contributions to the field of biological sciences, particularly for his research contributions and leadership to control Chagas Disease.”

Tarleton is a Regents Professor in the Department of Cellular Biology and UGA Athletic Association Distinguished Professor in Biological Sciences.

“It is indeed an honor to be acknowledged in this way – it reflects the strong efforts of many past and present members of the lab,” stated Tarleton, founder of the Center for Tropical and Emerging Global Diseases.

Since his undergraduate days, Tarleton’s research has focused on Trypanosoma cruzi infection, which causes the potentially fatal illness Chagas Disease. Historically, Tarleton’s research has attempted to answer broad questions such as how is immune control initiated and maintained during the infection, how does T. cruzi manage to avoid immune clearance and maintain an infection of decades in host, and what is the relationship between immunity, parasite persistence, and disease development. In an effort to answer these questions and more, Tarleton’s research group has developed tools to better study T. cruzi. They pioneered the use of the gene editing tool CRISPR in T. cruzi. Recently, they applied light sheet fluorescent microscopy to view infection in whole mouse organs. The Tarleton Research Group is also actively pursuing drug discovery for T. cruzi infection in a number of animal models including rodent, dog, and nonhuman primates. Their recent discovery of a dormancy stage in T. cruzi infections has revolutionized their drug treatment research, bringing them one step closer to finding a cure for this infection that affects at least 6 million people.

Tarleton’s work has largely been funded by the National Institutes of Health, the Wellcome Trust, the Burroughs Wellcome Fund, and partnerships with several pharmaceutical groups.

In addition to establishing the Center for Tropical and Emerging Global Diseases at UGA, he has been instrumental in organizing the Chagas Drug Discovery Consortium, which brings together U.S.-based laboratories with international groups. Tarleton is also the founder and current president of The Chagas Disease Foundation. He has been honored with a number of awards, including the Lamar Dodd Outstanding Researcher Award and being named a Burroughs Wellcome Fund Scholar in Molecular Parasitology. In 2017, he was elected as a Fellow of the American Academy of Microbiology.

“Rick’s election as a Fellow of AAAS is recognition of his immense contributions to the study of T. cruzi,” said Dennis Kyle, director of the Center for Tropical and Emerging Global Diseases. “His research has advanced our understanding of immune response to the pathogen, has developed new molecular approaches to study the parasite, and has accelerated drug discovery for Chagas Disease.”

Jessica Kissinger elected ASTMH Fellow

Jessica Kissinger
Jessica Kissinger (Photo by Peter Frey)

University of Georgia geneticist Jessica Kissinger has been elected a 2020 American Society of Tropical Medicine and Hygiene Fellow.

Kissinger is a Distinguished Research Professor in the Department of Genetics, part of the Franklin College of Arts and Sciences. She also holds appointments in the Institute of Bioinformatics and Center for Tropical and Emerging Global Diseases.

“I value belonging to a society that is focused on global health and lessening the burden of tropical infectious diseases, and I am truly honored to be recognized as a Fellow at a time when a focus on public health, science and climate change is so important for all of us,” said Kissinger.

Kissinger’s research focuses on parasite genomics and the biology of genome evolution. Her research group is trying to answer big questions such as how genomes evolve, what is the fate of horizontally transferred genes, which genes are phylogenetically restricted, and how do organellar genomes evolve? The answers to these questions will increase the understanding of parasite biology and help researchers identify potential drug and vaccine targets.

Kissinger’s research mainly focuses on Apicomplexan parasites, a group of parasites that include species that cause malaria, toxoplasmosis and cryptosporidiosis. Projects in her laboratory include the development of tools for data integration, data mining, comparative genomics and assessing the phylogenetic distribution of genes. Her research group oversees integrated genomic database resources, which are part of the Eukaryotic Pathogen, Vector and Host Informatics Resources (VEupathDB.org), funded by the National Institutes of Health. This resource provides the international research community with open access to data for many pathogenic and related organisms.

Kissinger’s research has been funded by the NIH, the Bill and Melinda Gates Foundation, the Defense Advanced Research Projects Agency, the Wellcome Trust, the United States Department of Agriculture, and the National Science Foundation. Notably, she is the joint principal investigator of a $38.4 million (if all options are exercised) NIH contract that supports VEupathDB.

Kissinger joined the faculty of UGA in 2001. She was a founding member of the Institute of Bioinformatics at UGA to facilitate cutting-edge interdisciplinary research in bioinformatics/computational biology and its applications. Kissinger has been recognized many times for research and leadership. She has been awarded a Creative Research Medal, Faculty Excellence in Diversity Leadership Award and the Richard F. Reiff Internationalization Award from UGA. In 2014, she was awarded a Special Visiting Professorship from Brazil’s national science research agency, and most recently, she was awarded a Fulbright U.S. Scholar award to teach and conduct research at Makerere University in Uganda.

“Being elected as a Fellow of the American Society of Tropical Medicine and Hygiene is recognition of a scientist that has made significant contributions to global public health,” said Dennis Kyle, director of the Center for Tropical and Emerging Global Diseases. “Dr. Kissinger richly deserves this award, and I look forward to her continued leadership in tropical medicine research.”

Towards a comprehensive research and development plan to support the control, elimination and eradication of neglected tropical diseases

To maximise the likelihood of success, global health programmes need repeated, honest appraisal of their own weaknesses, with research undertaken to address any identified gaps. There is still much to be learned to optimise work against neglected tropical diseases. To facilitate that learning, a comprehensive research and development plan is required. Here, we discuss how such a plan might be developed.

David Mabey, Ellen Agler, John H Amuasi, Leda Hernandez, T Déirdre Hollingsworth, Peter J Hotez, Patrick J Lammie, Mwelecele N Malecela, Sultani H Matendechero, Eric Ottesen, Richard O Phillips, John C Reeder, Célia Landmann Szwarcwald, Joseph P Shott, Anthony W Solomon, Andrew Steer, Soumya Swaminathan. Trans R Soc Trop Med Hyg. 2020 Nov 11;traa114. doi: 10.1093/trstmh/traa114.

The nucleocytosolic O-fucosyltransferase Spindly affects protein expression and virulence in Toxoplasma gondii

Once considered unusual, nucleocytoplasmic glycosylation is now recognized as a conserved feature of eukaryotes. While in animals O-GlcNAc transferase (OGT) modifies thousands of intracellular proteins, the human pathogen Toxoplasma gondii transfers a different sugar, fucose, to proteins involved in transcription, mRNA processing and signaling. Knockout experiments showed that TgSPY, an ortholog of plant SPINDLY and paralog of host OGT, is required for nuclear O-fucosylation. Here we verify that TgSPY is the nucleocytoplasmic O-fucosyltransferase (OFT) by 1) complementation with TgSPY-MYC3, 2) its functional dependence on amino acids critical for OGT activity, and 3) its ability to O-fucosylate itself and a model substrate and to specifically hydrolyze GDP-Fuc. While many of the endogenous proteins modified by O-Fuc are important for tachyzoite fitness, O-fucosylation by TgSPY is not essential. Growth of Δspy tachyzoites in fibroblasts is modestly affected, despite marked reductions in the levels of ectopically-expressed proteins normally modified with O-fucose. Intact TgSPY-MYC3 localizes to the nucleus and cytoplasm, whereas catalytic mutants often displayed reduced abundance. Δspy tachyzoites of a luciferase-expressing type II strain exhibited infection kinetics in mice similar to wild type but increased persistence in the chronic brain phase, potentially due to an imbalance of regulatory protein levels. The modest changes in parasite fitness in vitro and in mice, despite profound effects on reporter protein accumulation, and the characteristic punctate localization of O-fucosylated proteins, suggest that TgSPY controls the levels of proteins to be held in reserve for response to novel stresses.

Giulia Bandini, Carolina Agop-Nersesian, Hanke van der Wel, Msano Mandalasi , Hyun W Kim, Christopher M West, John Samuelson. J Biol Chem. 2020 Nov 6;jbc.RA120.015883. doi: 10.1074/jbc.RA120.015883.

Outbreak News Today Interviews Rick Tarleton

Recently, Dr. Rick Tarleton was interviewed by Outbreak News Today about his recently published study in Science Translational Medicine.

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Diagnostics and the neglected tropical diseases roadmap: setting the agenda for 2030

Accurate and reliable diagnostic tools are an essential requirement for neglected tropical diseases (NTDs) programmes. However, the NTD community has historically underinvested in the development and improvement of diagnostic tools, potentially undermining the successes achieved over the last 2 decades. Recognizing this, the WHO, in its newly released draft roadmap for NTD 2021-2030, has identified diagnostics as one of four priority areas requiring concerted action to reach the 2030 targets. As a result, WHO established a Diagnostics Technical Advisory Group (DTAG) to serve as the collaborative mechanism to drive progress in this area. Here, the purpose and role of the DTAG are described in the context of the challenges facing NTD programmes.

Ashley A Souza, Camilla Ducker, Daniel Argaw, Jonathan D King, Anthony W Solomon, Marco A Biamonte, Rhea N Coler, Israel Cruz, Veerle Lejon, Bruno Levecke, Fabricio K Marchini, Michael Marks, Pascal Millet, Sammy M Njenga, Rahmah Noordin, René Paulussen, Esvawaran Sreekumar, Patrick J Lammie. Trans R Soc Trop Med Hyg. 2020 Nov 9;traa118. doi: 10.1093/trstmh/traa118.