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Author: Donna Huber

Hepatocytes and the art of killing Plasmodium softly

Figure 1. The gap in our understanding of how hepatocytes eliminate Plasmodium.
Figure 1. The gap in our understanding of how hepatocytes eliminate Plasmodium.

 

The Plasmodium parasites that cause malaria undergo asymptomatic development in the parenchymal cells of the liver, the hepatocytes, prior to infecting erythrocytes and causing clinical disease. Traditionally, hepatocytes have been perceived as passive bystanders that allow hepatotropic pathogens such as Plasmodium to develop relatively unchallenged. However, now there is emerging evidence suggesting that hepatocytes can mount robust cell-autonomous immune responses that target Plasmodium, limiting its progression to the blood and reducing the incidence and severity of clinical malaria. Here we discuss our current understanding of hepatocyte cell-intrinsic immune responses that target Plasmodium and how these pathways impact malaria.

Camila Marques-da-Silva, Clyde Schmidt-Silva, Samarchith P Kurup. Trends Parasitol. 2024 May 6:S1471-4922(24)00086-2. doi: 10.1016/j.pt.2024.04.004.

Identification of a viral gene essential for the genome replication of a domesticated endogenous virus in ichneumonid parasitoid wasps

Fig 6. RNAi knockdown of U16.
RNAi knockdown of U16.

 

Thousands of endoparasitoid wasp species in the families Braconidae and Ichneumonidae harbor “domesticated endogenous viruses” (DEVs) in their genomes. This study focuses on ichneumonid DEVs, named ichnoviruses (IVs). Large quantities of DNA-containing IV virions are produced in ovary calyx cells during the pupal and adult stages of female wasps. Females parasitize host insects by injecting eggs and virions into the body cavity. After injection, virions rapidly infect host cells which is followed by expression of IV genes that promote the successful development of wasp offspring. IV genomes consist of two components: proviral segment loci that serve as templates for circular dsDNAs that are packaged into capsids, and genes from an ancestral virus that produce virions. In this study, we generated a chromosome-scale genome assembly for Hyposotor didymator that harbors H. didymator ichnovirus (HdIV). We identified a total of 67 HdIV loci that are amplified in calyx cells during the wasp pupal stage. We then focused on an HdIV gene, U16, which is transcribed in calyx cells during the initial stages of replication. Sequence analysis indicated that U16 contains a conserved domain in primases from select other viruses. Knockdown of U16 by RNA interference inhibited virion morphogenesis in calyx cells. Genome-wide analysis indicated U16 knockdown also inhibited amplification of HdIV loci in calyx cells. Altogether, our results identified several previously unknown HdIV loci, demonstrated that all HdIV loci are amplified in calyx cells during the pupal stage, and showed that U16 is required for amplification and virion morphogenesis.

Ange Lorenzi, Fabrice Legeai, Véronique Jouan, Pierre-Alain Girard, Michael R Strand, Marc Ravallec, Magali Eychenne, Anthony Bretaudeau, Stéphanie Robin, Jeanne Rochefort, Mathilde Villegas, Gaelen R Burke, Rita Rebollo, Nicolas Nègre, Anne-Nathalie Volkoff. PLoS Pathog. 2024 Apr 25;20(4):e1011980. doi: 10.1371/journal.ppat.1011980.

 

UGA geneticist gets to take risks with new seed grant

By Donna Huber

photo of Tania Rozario standing in front of a purple shrub.
Assistant Professor Tania Rozario has received a seed grant from the Hypothesis Fund to develop a new approach to advance tapeworm research, particularly on the little understood topic of regeneration.

Tania Rozario, assistant professor in the Department of Genetics and member of the Center for Tropical and Emerging Global Diseases, recently received a seed grant from the Hypothesis Fund to develop a new approach toward advancing tapeworm research. Her natural inquisitiveness and willingness to tackle tough questions has led to this moment.

As a child in Malaysia Rozario was fascinated with the world around her. Her interest was fostered by her grandfather who was an amateur botanist and science teacher. After reading about NASA in a kid’s science magazine, she wrote a letter to them. Their willingness to engage with her inspired her to see science as a real career choice.

“I was exposed to science at an early age,” said Rozario. “But what had the biggest impact on my decision to become a scientist was doing undergraduate research.”

By the time she enrolled in graduate school at the University of Virginia, she knew she wanted to study regeneration. She focused on developmental biology and embryology as she needed a strong foundation in these disciplines to pursue her future research. She returned to regeneration during her post-doctoral training in the Newmark laboratory at the Morgridge Institute for Research. It was then that she started her work in tapeworm regeneration.

“I was drawn to the untapped potential in tapeworms to understand basic biological functions,” she said. “Tapeworms have a complex lifecycle and are difficult to study in the lab – so there’s a challenge there too.”

The mechanisms of regeneration are poorly understood in tapeworms. Stem cells are responsible for regeneration. The Rozario lab wants to know what is special about the stem cells and signals in the “neck” as this tissue is the only tissue capable of regenerating new segments, despite the fact that there are stem cells everywhere in the tapeworm body.

micrograph of rate tapeworm
Rozario’s work is shedding light on tapeworm biology and the broader understanding of stem cells in other organisms. Here, a distribution of cycling stem cells (multicolored) is shown within the regeneration-competent tapeworm neck. (Photo courtesy of Tania Rozario)

“Tapeworms can grow very large, but regeneration only happens from a tiny part,” explained Rozario. “We want to know what genes are controlling it but right now we don’t have sufficient tools.”

With the gene-editing tool CRISPR/Cas, researchers have been making remarkable strides in understanding genes in many organisms. However, there is no evidence that transgenesis, the process in which genes are inserted into an organism, works in tapeworms.

This is where the seed grant from the Hypothesis Fund comes in.

“They have scouts who are looking for unconventional science – research where although there may be risk or uncertainty that it will work, it could have a transformational effect if it does,” said Rozario.

The Hypothesis Fund provides seed grants for bold ideas at the earliest stage of research, often before any preliminary data have been generated.

“There are a number of barriers to getting CRISPR/Cas to work in an organism,” said Rozario in response to the risk of this project.

She lists three things that are needed to successfully use CRISPR/Cas: the right type of organism, access to an early development stage, and the expertise.

“We are in a good position to make this work,” further explained Rozario.

The Rozario lab has successfully developed a number of tools to better study the tapeworm in the lab. Since tapeworms produce both male and female gametes in every segment there is plenty of early development stage material to work with.

“Thanks to this gift, we are able to bring in post-doctoral researcher Olufemi Akinkuotu from the University of Pennsylvania School of Veterinary Medicine,” said Rozario. “He has specific training in developing gene-editing tools in parasitic nematodes, which are distantly related to tapeworms but share many parallel challenges.”

While there is still a risk that CRISPR/Cas won’t work in tapeworms, if it does the payoff could be huge – not only for understanding the basic biology of tapeworms, but to further our understanding of stem cells in other organisms.

This story first appeared at https://research.uga.edu/news/uga-geneticist-gets-to-take-risks-with-new-seed-grant/

 

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.