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Author: Donna Huber

Extended blood stage sensitivity profiles of Plasmodium cynomolgi to doxycycline and tafenoquine, as a model for Plasmodium vivax

Figure 1 Mean IC50 concentrations (nM) of chloroquine, doxycycline, piperaquine, and tafenoquine using 48-, 72- and 96-hour assays.
Mean IC50 concentrations (nM) of chloroquine, doxycycline, piperaquine, and tafenoquine using 48-, 72- and 96-hour assays.

Testing Plasmodium vivax antimicrobial sensitivity is limited to ex vivo schizont maturation assays, which preclude determining the IC50s of delayed action antimalarials such as doxycycline. Using Plasmodium cynomolgi as a model for P. vivax, we determined the physiologically significant delayed death effect induced by doxycycline [IC50(96 h), 1,401 ± 607 nM]. As expected, IC50(96 h) to chloroquine (20.4 nM), piperaquine (12.6 µM), and tafenoquine (1,424 nM) were not affected by extended exposure.

Peter Christensen, Rosy Cinzah, Rossarin Suwanarusk, Adeline Chiew Yen Chua, Osamu Kaneko, Dennis E Kyle, Htin Lin Aung, Jessica Matheson, Pablo Bifani, Laurent Rénia, Gregory M Cook, Georges Snounou, Bruce Russell. Antimicrob Agents Chemother. 2024 Apr 8:e0028024. doi: 10.1128/aac.00280-24.

Two CTEGD faculty members receive Creative Research Awards

Jessica Kissinger and Dennis Kyle received the Lamar Dodd Creative Research Award during UGA’s Honors Week. The award recognizes established investigators whose overall scholarly body of work has had a major impact on the field of study and has established the investigator’s international reputation as a leader in the field.

Jessica Kissinger, Distinguished Research Professor in the Franklin College of Arts and Sciences’ genetics department and former director of the UGA Institute of Bioinformatics, has focused her interdisciplinary career on the question of how parasites evolve. She has been a driving force behind the groundbreaking effort to create and maintain novel bioinformatics databases covering omics data for hundreds of dangerous pathogens. The Eukaryotic Pathogen, Vector, and Host Informatics Resources knowledgebase (VEuPathDB.org) is an integrated, centralized resource for data mining on more than 500 organisms. Databases searches are free, permitting researchers to gain insights into and test hypotheses that may pave the way for new approaches to treating or preventing diseases such as malaria and Cryptosporidium (a waterborne parasite). Kissinger has used the databases and other bioinformatics tools to make remarkable discoveries.

Dennis E. Kyle, professor of cellular biology and infectious diseases in the Franklin College of Arts and Sciences and the College of Veterinary Medicine, is one of the top parasitologists in the world. Kyle serves as director of the Center for Tropical and Emerging Global Diseases, and some of his most recent work focuses on discovery of new drugs that eliminate dormant vivax malaria that can linger in the liver. His group has discovered new drug series that target the dormant liver stages and is moving these novel therapeutics through preclinical studies. He also works on Naegleria fowleri, a rare but deadly parasite known as “brain-eating amoebae.” More than 97% of people infected with these amoebae die within two weeks. Kyle has conducted research into that pathogen, leading to effective repurposed drugs and the first rapid, sensitive diagnostic method.

 

First appeared in 2024 Research Awards

The Unfortunate Abundance of Trypanosoma cruzi in Naturally Infected Dogs and Monkeys Provides Unique Opportunities to Advance Solutions for Chagas Disease

Trypanosoma cruzi, the protozoan parasite and cause of Chagas disease, is widely distributed in many vertebrate and triatomine species throughout North, Central, and South America. Variations in housing quality largely determines human infection risk in the Americas. However, the southern U.S. contains widespread, infected triatomine vectors and captive species and domesticated animals with active T. cruzi infection or at high risk of becoming infected and developing Chagas disease. There is a critical need for better detection and intervention strategies, principally focused on human infection throughout the Americas, but mainly in the U.S., for high-value dogs employed in government and other work. In addition to this economic impact, the concentration of largely unavoidable T. cruzi infections in U.S. dogs provides an incomparable opportunity to answer questions related to T. cruzi infection and Chagas disease that are impossible or unethical to address in humans. As the course of T. cruzi infection and Chagas disease, the immune response to infection, and the response to therapeutics are highly similar across the range of mammalian host species, information obtained from studies in other species can directly inform researchers on how to best detect, manage, and treat T. cruzi infection and Chagas disease in humans.

Rick L. Tarleton, Ashley B. Saunders, Bruno Lococo, Maria Gabriela Alvarez Gianni, Susana Laucella, Carolyn L. Hodo, Gregory K. Wilkerson, Sarah A. Hamer. Zoonoses. 2024. Vol. 4(1). DOI: 10.15212/ZOONOSES-2024-0005

What is new in FungiDB: a web-based bioinformatics platform for omics-scale data analysis for fungal and oomycete species

New data in FungiDB since FungiDB Release 37.
New data in FungiDB since FungiDB Release 37.

 

FungiDB (https://fungidb.org) serves as a valuable online resource that seamlessly integrates genomic and related large-scale data for a wide range of fungal and oomycete species. As an integral part of the VEuPathDB Bioinformatics Resource Center (https://veupathdb.org), FungiDB continually integrates both published and unpublished data addressing various aspects of fungal biology. Established in early 2011, the database has evolved to support 674 datasets. The datasets include over 300 genomes spanning various taxa (e.g. Ascomycota, Basidiomycota, Blastocladiomycota, Chytridiomycota, Mucoromycota, as well as Albuginales, Peronosporales, Pythiales, and Saprolegniales). In addition to genomic assemblies and annotation, over 300 extra datasets encompassing diverse information, such as expression and variation data, are also available. The resource also provides an intuitive web-based interface, facilitating comprehensive approaches to data mining and visualization. Users can test their hypotheses and navigate through omics-scale datasets using a built-in search strategy system. Moreover, FungiDB offers capabilities for private data analysis via the integrated VEuPathDB Galaxy platform. FungiDB also permits genome improvements by capturing expert knowledge through the User Comments system and the Apollo genome annotation editor for structural and functional gene curation. FungiDB facilitates data exploration and analysis and contributes to advancing research efforts by capturing expert knowledge for fungal and oomycete species.

Evelina Y Basenko, Achchuthan Shanmugasundram, Ulrike Böhme, David Starns, Paul A Wilkinson, Helen R Davison, Kathryn Crouch, Gareth Maslen, Omar S Harb, Beatrice Amos, Mary Ann McDowell, Jessica C Kissinger, David S Roos, Andrew Jones. Genetics. 2024 Mar 26:iyae035. doi: 10.1093/genetics/iyae035

Positive clinical outcome using a modified dosing regimen of benznidazole in dogs at high risk for infection or acutely infected with Trypanosoma cruzi

Serum cardiac troponin I results for the 4 dogs.
Serum cardiac troponin I results for the 4 dogs.

 

Trypanosoma cruzi infection in dogs can cause heart failure and sudden death with few treatment options available. A litter of 4 dogs living in a T cruzi endemic area were randomized to prophylaxis and nonprophylaxis groups as part of a study evaluating a modified benznidazole dosing regimen administered twice weekly to prevent T cruzi infection during a vector transmission season. The 2 dogs that received prophylaxis remained healthy without T cruzi infection or cardiac disease for >2 years. One dog that did not receive prophylaxis died unexpectedly with acute T cruzi-induced pancarditis, and the second dog tested positive for T cruzi and developed complex arrhythmias with markedly increased cardiac troponin I and improved with a higher benznidazole treatment dose. Although the small sample size precludes definitive conclusions, we describe the potential clinical benefit of prophylactic and early treatment with modified benznidazole dosing regimens for dogs with T cruzi infection.

Sukjung Lim, Stephanie Collins, Sarah A Hamer, Rick L Tarleton, Ashley B Saunders. J Vet Intern Med. 2024 Mar 18. doi: 10.1111/jvim.17028.

Two CTEGD trainees receive AHA fellowships

Photos of Graduate student Baihetiya “Barna” Baierna and postdoctoral fellow Mayara Bertolini
Graduate student Baihetiya “Barna” Baierna and postdoctoral fellow Mayara Bertolini received fellowships from the American Heart Association, supporting their research and education. Both are studying parasites in the University of Georgia’s Center for Tropical and Emerging Global Diseases. (Photos courtesy of CTEGD)

 

Baihetiya “Barna” Baierna, a cellular biology graduate student in Silvia Moreno’s laboratory, received an American Heart Association Pre-doctoral Fellowship. It will fund her training for the next two years as she studies the mitochondrion of Toxoplasma gondii.

Baierna grew up wanting to follow in her mother’s footsteps as a scientist.

“My mom worked for the regional CDC in China and I was interested in science since a young age,” Baierna said.

After completing her undergraduate degree in biochemistry, she was sure she wanted to continue her training in graduate school. After being accepted into the Department of Cellular Biology program, she joined the Moreno Laboratory.

Toxoplasma gondii infects approximately one third of the world human population. The infection can cause serious complications in people with a suppressed immune system. Baierna’s research aims at validating novel T. gondii mitochondrial proteins as novel chemotherapeutic targets for improved chemotherapy of toxoplasmosis. This is important because the present drugs are not effective against the chronic stages of the infection. She has developed novel strategies for the discovery of new mitochondrial proteins and already found a novel enzymatic activity highly divergent from the mammalian counterpart. The outcome of this project will expand the knowledge of the T. gondii mitochondrion, as well as helping with the identification of viable drug targets.

“An AHA Fellowship is a very competitive award, but Barna deserves it and we are very proud of her,” said Moreno.

“Preparing the grant proposal was a great learning experience and it will help me with my career development,” said Baierna, “I’m very happy that it was funded.”

Mayara Bertolini, a post-doctoral fellow in Roberto Docampo’s laboratory, received an American Heart Association Post-doctoral Fellowship. It will support her training for one year.

After receiving her bachelor’s degree, Bertolini obtained her master’s degree in a lab that Docampo had set up in Brazil working on T. cruzi. From there she decided to pursue her Ph.D. at the University of Georgia. She completed her Ph.D. in 2023.

Trypanosoma cruzi is the parasite that causes Chagas disease. At least 6 million people, mostly in South America, are infected with the parasite. T. cruzi is transmitted to humans through the feces of an insect commonly referred to as the kissing bug. While Chagas disease was first discovered in 1909, there is still a lot that is unknown about the biology of T. cruzi. This lack of knowledge has hindered drug development. Bertolini’s project is focused on the role of polyphosphate during the Trypanosoma cruzi life cycle.

“This is the second fellowship from the AHA that Mayara has received. She got a two-year pre-doctoral fellowship before and has done outstanding work,” said Docampo.

“AHA Fellowships are very competitive and I’m thrilled my proposal was selected,” said Bertolini. “In addition to supporting my training, there is support for career development and networking opportunities.”

 

The story originally appeared at https://research.uga.edu/news/two-ctegd-trainees-receive-aha-fellowships/

Genomic and virulence analysis of in vitro cultured Cryptosporidium parvum

Fig 1. Diagramatic section through the hollow fiber bioreactor.
Fig 1. Diagramatic section through the hollow fiber bioreactor.

 

Recent advances in the in vitro cultivation of Cryptosporidium parvum using hollow fiber bioreactor technology (HFB) have permitted continuous growth of parasites that complete all life cycle stages. The method provides access to all stages of the parasite and provides a method for non-animal production of oocysts for use in clinical trials. Here we examined the effect of long-term (>20 months) in vitro culture on virulence-factors, genome conservation, and in vivo pathogenicity of the host by in vitro cultured parasites. We find low-level sequence variation that is consistent with that observed in calf-passaged parasites. Further using a calf model infection, oocysts obtained from the HFB caused diarrhea of the same volume, duration and oocyst shedding intensity as in vivo passaged parasites.

Nigel Yarlett, Mary Morada, Deborah A Schaefer, Kevin Ackman, Elizabeth Carranza, Rodrigo de Paula Baptista, Michael W Riggs, Jessica Kissinger. PLoS Pathog. 2024 Feb 28;20(2):e1011992. doi: 10.1371/journal.ppat.1011992.

Regulation of Calcium entry by cyclic GMP signaling in Toxoplasma gondii

Figure 1. Calcium entry through the plasma membrane of extracellular T. gondii tachyzoites.
Figure 1. Calcium entry through the plasma membrane of extracellular T. gondii tachyzoites.

 

Ca2+ signaling impacts almost every aspect of cellular life. Ca2+ signals are generated through the opening of ion channels that permit the flow of Ca2+ down an electrochemical gradient. Cytosolic Ca2+ fluctuations can be generated through Ca2+ entry from the extracellular milieu or release from intracellular stores. In Toxoplasma gondii, Ca2+ ions play critical roles in several essential functions for the parasite like invasion of host cells, motility and egress. Plasma membrane Ca2+ entry in T. gondii was previously shown to be activated by cytosolic calcium and inhibited by the voltage-operated Ca2+ channel blocker nifedipine. However, Ca2+ entry in T. gondii did not show the classical characteristics of store regulation. In this work, we characterized the mechanism by which cytosolic Ca2+ regulates plasma membrane Ca2+ entry in extracellular T. gondii tachyzoites loaded with the Ca2+ indicator Fura 2. We compared the inhibition by nifedipine with the effect of the broad spectrum TRP channel inhibitor, anthranilic acid or ACA and we find that both inhibitors act on different Ca2+ entry activities. We demonstrate, using pharmacological and genetic tools, that an intracellular signaling pathway engaging cyclicGMP (cGMP), protein kinase G (PKG), Ca2+ and the phosphatidyl inositol phospholipase C (PI-PLC) affects Ca2+ entry and we present a model for crosstalk between cGMP and cytosolic Ca2+ for the activation of T. gondii‘s lytic cycle traits.

Miryam A Hortua Triana, Karla M Márquez-Nogueras, Mojtaba Sedigh Fazli, Shannon Quinn, Silvia N J Moreno. J Biol Chem. 2024 Feb 19:105771. doi: 10.1016/j.jbc.2024.105771

Trainee Spotlight: Corey Rennolds

Corey Rennolds

 

My name is Corey Rennolds, and I’ve been a postdoctoral researcher in Tania Rozario’s lab at UGA since August 2022. I’m originally from Cobb County, GA, where I went to grade school, received my B.S. in Biology from Georgia Tech in 2013, and completed my PhD at the University of Maryland, College Park in 2022.

What made you want to study science?
The big bucks, baby!! More honestly, I enjoy learning how things work for its own sake, and I liked the idea of a career spent always learning more about how things in the world work. I started as an undergraduate in engineering but quickly switched to biology when I realized that I was more interested in natural systems than artificial ones (and that I wasn’t very good at calculus). I have other interests of course, but science translates the most smoothly of those into a stable and rewarding way to make a living.

Why did you choose UGA?
I’m originally from the Atlanta area and spent a lot of time in Athens when I was an undergraduate, even though I went to Tech. Now living and working here feels like coming home for me. I finished my PhD and wanted to continue in a research-oriented direction as a postdoc in an academic setting, and UGA is a big, well-funded institution with a strong biology contingent and several faculty in the ballpark of my more narrow expertise. Altogether, it seemed like a good fit.

What is your project/research focus and why did you choose this research focus?
Dr. Rozario learned during her own postdoctoral work that the rat tapeworm Hymenolepis diminuta requires a population of stem cells maintained in the adult worm in order to grow and regenerate, but there was little information on how these cells are activated, how many different varieties there are, their plasticity, and how they differentiate into mature tissue types. Dr. Rozario wanted to hire a postdoc with experience in transcriptomics and regenerative biology in non-model organisms, which is fortunately my background. I thought the project was really interesting with opportunity to do novel work that would stand out. It also gives me the chance to learn a lot of cutting-edge techniques that can be valuable for my research in the long term.

Have you received any awards or honors?
Aside from the T32 postdoctoral fellowship through the CTEGD, I received a few scholarships, fellowships, and other awards during graduate school, including small research grants from Sigma Xi, the Cosmos Club, and Washington Biologists’ Field Club. I would also be remiss not to mention my first-place finish in the most recent CTEGD chili cook-off.

What are your career goals?
I spent most of graduate school as a TA (tip for prospective graduate students: ask your PI about funding!) and so racked up plenty of experience in teaching and discovered that I really enjoy doing it. I want teaching to be a significant part of my career activities going forward, as opposed to just full-time research. Research-wise, though, I am interested in building an independent research program focused on bridging evolutionary-developmental biology with comparative and ecological physiology. To put it simply, I want to study how living things grow, develop, and repair themselves, where and how they get the resources to do these things, and how those processes are affected by environmental factors, including over evolutionary timescales. Working with intestinal parasites is definitely an interesting and challenging context for thinking about these sorts of broad questions.

What is your favorite thing about UGA and Athens?
Athens is close enough to Atlanta to access its amenities but far enough away to be its own ecosystem free of the sprawl. It’s big enough to have a little of everything, including a vibrant and diverse arts scene, but small enough to get to know most of the people in whatever sphere you want to be involved in. The university offers plenty of opportunities for both intellectual stimulation and less-intellectual partying. The traffic isn’t too bad.

Any advice for a student interested in this field?
Don’t settle too much. It is perfectly fine to have standards during your education and assert yourself when called for. You should study what you enjoy, attend school somewhere you want to be, and work with people you get along with. Not everything will be perfect and you should learn when to compromise, of course, but it’s your life and your career. If something isn’t working out, make a change, and be open to alternative paths—if I didn’t take the initiative to change course when I did, I wouldn’t be a biologist now. Think carefully about what is in your best interest personally and professionally in both the short and long term. Also, learn when to identify opportunities to learn something useful or gain valuable experience. In CTEGD, there are a lot of different technical resources, training and professional development opportunities, and diverse faculty expertise; make use of all these things, it’s what they’re there for!

 

Support trainees like Corey by giving today to the Center for Tropical & Emerging Global Diseases.

In Vitro Antimalarial Activity of Trichothecenes against Liver and Blood Stages of Plasmodium Species

graphical representation of abstract

Trichothecenes (TCNs) are a large group of tricyclic sesquiterpenoid mycotoxins that have intriguing structural features and remarkable biological activities. Herein, we focused on three TCNs (anguidine, verrucarin A, and verrucarol) and their ability to target both the blood and liver stages of Plasmodium species, the parasite responsible for malaria. Anguidine and verrucarin A were found to be highly effective against the blood and liver stages of malaria, while verrucarol had no effect at the highest concentration tested. However, these compounds were also found to be cytotoxic and, thus, not selective, making them unsuitable for drug development. Nonetheless, they could be useful as chemical probes for protein synthesis inhibitors due to their direct impact on parasite synthesis processes.

Prakash T Parvatkar, Steven P Maher, Yingzhao Zhao, Caitlin A Cooper, Sagan T de Castro, Julie Péneau, Amélie Vantaux, Benoît Witkowski, Dennis E Kyle, Roman Manetsch. J Nat Prod. 2024 Jan 23. doi: 10.1021/acs.jnatprod.3c01019.