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Jessica Kissinger elected as AAAS Fellow

Donna Huber on January 27, 2022

Three University of Georgia faculty have been named Fellows of the American Association for the Advancement of Science.

In a tradition stretching back to 1874, these individuals are elected annually by the AAAS Council for their extraordinary achievements leading to the advancement of science. Fellows must have been AAAS members for at least four years.

“Researchers are elected Fellows of the AAAS by their peers in recognition of significant contributions to their field,” said Karen Burg, vice president for research. “As we expand our research and innovation ecosystem, it’s exciting to see our faculty continue to be honored for their superb scholarship. I congratulate all of them on this wonderful achievement.”

The 2021 class of AAAS Fellows includes 564 scientists, engineers and innovators spanning 24 scientific disciplines who are being recognized for their scientifically and socially distinguished achievements. The new Fellows will be honored at the annual AAAS meeting in Philadelphia, Feb. 17-20. Along with the rest of their 2021 class, UGA’s three new Fellows will receive an official certificate and a gold and blue rosette pin whose colors represent science and engineering.

Including these three, 37 faculty at UGA are Fellows of the American Association for the Advancement of Science.

UGA’s 2021 AAAS Fellows are:

James E. Byers: Meigs Distinguished Teaching Professor and associate dean for research and operations in the Odum School of Ecology, Byers was selected for distinguished contributions to the field of ecology, particularly in invasion biology, parasite ecology, ecosystem engineering and range boundaries in marine environments, as well as excellence in teaching.

Jessica Kissinger: Distinguished Research Professor of genetics in the Franklin College of Arts and Sciences and a member of the Center for Tropical and Emerging Global Diseases, Kissinger was selected for distinguished contributions to the field of the evolution of infectious diseases, particularly for bioinformatics approaches.

Patricia Yager: Professor of marine science in the Franklin College, Yager was selected for outstanding work on climate-driven processes and their impact on marine ecosystems.

To view a list of all AAAS Fellows from UGA, visit the Office of Research website.

The story by Ian Bennet first appeared on UGA Today.

Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi

Donna Huber on December 30, 2021

Background: Kra monkeys (Macaca fascicularis), a natural host of Plasmodium knowlesi, control parasitaemia caused by this parasite species and escape death without treatment. Knowledge of the disease progression and resilience in kra monkeys will aid the effective use of this species to study mechanisms of resilience to malaria. This longitudinal study aimed to define clinical, physiological and pathological changes in kra monkeys infected with P. knowlesi, which could explain their resilient phenotype.

Methods: Kra monkeys (n = 15, male, young adults) were infected intravenously with cryopreserved P. knowlesi sporozoites and the resulting parasitaemias were monitored daily. Complete blood counts, reticulocyte counts, blood chemistry and physiological telemetry data (n = 7) were acquired as described prior to infection to establish baseline values and then daily after inoculation for up to 50 days. Bone marrow aspirates, plasma samples, and 22 tissue samples were collected at specific time points to evaluate longitudinal clinical, physiological and pathological effects of P. knowlesi infections during acute and chronic infections.

Results: As expected, the kra monkeys controlled acute infections and remained with low-level, persistent parasitaemias without anti-malarial intervention. Unexpectedly, early in the infection, fevers developed, which ultimately returned to baseline, as well as mild to moderate thrombocytopenia, and moderate to severe anaemia. Mathematical modelling and the reticulocyte production index indicated that the anaemia was largely due to the removal of uninfected erythrocytes and not impaired production of erythrocytes. Mild tissue damage was observed, and tissue parasite load was associated with tissue damage even though parasite accumulation in the tissues was generally low.

Conclusions: Kra monkeys experimentally infected with P. knowlesi sporozoites presented with multiple clinical signs of malaria that varied in severity among individuals. Overall, the animals shared common mechanisms of resilience characterized by controlling parasitaemia 3-5 days after patency, and controlling fever, coupled with physiological and bone marrow responses to compensate for anaemia. Together, these responses likely minimized tissue damage while supporting the establishment of chronic infections, which may be important for transmission in natural endemic settings. These results provide new foundational insights into malaria pathogenesis and resilience in kra monkeys, which may improve understanding of human infections.

Mariko S Peterson, Chester J Joyner, Jessica A Brady, Jennifer S Wood, Monica Cabrera-Mora, Celia L Saney, Luis L Fonseca, Wayne T Cheng, Jianlin Jiang, Stacey A Lapp, Stephanie R Soderberg, Mustafa V Nural, Jay C Humphrey, Allison Hankus, Deepa Machiah, Ebru Karpuzoglu, Jeremy D DeBarry, MaHPIC-Consortium; Rabindra Tirouvanziam, Jessica C Kissinger, Alberto Moreno, Sanjeev Gumber, Eberhard O Voit, Juan B Gutiérrez, Regina Joice Cordy, Mary R Galinski. Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi. Malar J 20, 486 (2021). https://doi.org/10.1186/s12936-021-03925-6

Long-read assembly and comparative evidence-based reanalysis of Cryptosporidium genome sequences reveals expanded transporter repertoire and duplication of entire chromosome ends including subtelomeric regions

Donna Huber on November 11, 2021

Cryptosporidiosis is a leading cause of waterborne diarrheal disease globally and an important contributor to mortality in infants and the immunosuppressed. Despite its importance, the Cryptosporidium community has only had access to a good, but incomplete, Cryptosporidium parvum IOWA reference genome sequence. Incomplete reference sequences hamper annotation, experimental design and interpretation. We have generated a new C. parvum IOWA genome assembly supported by PacBio and Oxford Nanopore long-read technologies and a new comparative and consistent genome annotation for three closely related species C. parvum, Cryptosporidium hominis and Cryptosporidium tyzzeri We made 1,926 C. parvum annotation updates based on experimental evidence. They include new transporters, ncRNAs, introns and altered gene structures. The new assembly and annotation revealed a complete Dnmt2 methylase ortholog. Comparative annotation between C. parvum, C. hominis and C. tyzzeri revealed that most “missing” orthologs are found suggesting that the biological differences between the species must result from gene copy number variation, differences in gene regulation and single nucleotide variants (SNVs). Using the new assembly and annotation as reference, 190 genes are identified as evolving under positive selection, including many not detected previously. The new C. parvum IOWA reference genome assembly is larger, gap free and lacks ambiguous bases. This chromosomal assembly recovers all 16 chromosome ends, 13 of which are contiguously assembled. The three remaining chromosome ends are provisionally placed. These ends represent duplication of entire chromosome ends including subtelomeric regions revealing a new level of genome plasticity that will both inform and impact future research.

Rodrigo P Baptista, Yiran Li, Adam Sateriale, Karen L Brooks, Alan Tracey, Mandy J Sanders, Brendan R E Ansell, Aaron R Jex, Garrett W Cooper, Ethan D Smith, Rui Xiao, Jennifer E Dumaine, Peter Georgeson, Bernard Pope, Matthew Berriman, Boris Striepen, James A Cotton, Jessica C Kissinger. Genome Res. 2021 Nov 11;gr.275325.121. doi: 10.1101/gr.275325.121.

VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center

Donna Huber on October 28, 2021

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.

Beatrice Amos, Cristina Aurrecoechea, Matthieu Barba, Ana Barreto, Evelina Y Basenko, Wojciech Bażant, Robert Belnap, Ann S Blevins, Ulrike Böhme, John Brestelli, Brian P Brunk, Mark Caddick, Danielle Callan, Lahcen Campbell, Mikkel B Christensen, George K Christophides, Kathryn Crouch, Kristina Davis, Jeremy DeBarry, Ryan Doherty, Yikun Duan, Michael Dunn, Dave Falke, Steve Fisher, Paul Flicek, Brett Fox, Bindu Gajria, Gloria I Giraldo-Calderón, Omar S Harb, Elizabeth Harper, Christiane Hertz-Fowler, Mark J Hickman, Connor Howington, Sufen Hu, Jay Humphrey, John Iodice, Andrew Jones, John Judkins, Sarah A Kelly, Jessica C Kissinger, Dae Kun Kwon, Kristopher Lamoureux, Daniel Lawson, Wei Li, Kallie Lies, Disha Lodha, Jamie Long, Robert M MacCallum, Gareth Maslen, Mary Ann McDowell, Jaroslaw Nabrzyski, David S Roos, Samuel S C Rund, Stephanie Wever Schulman, Achchuthan Shanmugasundram, Vasily Sitnik, Drew Spruill, David Starns, Christian J Stoeckert, Sheena Shah Tomko, Haiming Wang, Susanne Warrenfeltz, Robert Wieck, Paul A Wilkinson, Lin Xu, Jie Zheng. Nucleic Acids Res. 2021 Oct 28;gkab929. doi: 10.1093/nar/gkab929.

Challenges for Cryptosporidium Population Studies

Donna Huber on June 10, 2021

Cryptosporidiosis is ranked sixth in the list of the most important food-borne parasites globally, and it is an important contributor to mortality in infants and the immunosuppressed. Recently, the number of genome sequences available for this parasite has increased drastically. The majority of the sequences are derived from population studies of Cryptosporidium parvum and Cryptosporidium hominis, the most important species causing disease in humans. Work with this parasite is challenging since it lacks an optimal, prolonged, in vitro culture system, which accurately reproduces the in vivo life cycle. This obstacle makes the cloning of isolates nearly impossible. Thus, patient isolates that are sequenced represent a population or, at times, mixed infections. Oocysts, the lifecycle stage currently used for sequencing, must be considered a population even if the sequence is derived from single-cell sequencing of a single oocyst because each oocyst contains four haploid meiotic progeny (sporozoites). Additionally, the community does not yet have a set of universal markers for strain typing that are distributed across all chromosomes. These variables pose challenges for population studies and require careful analyses to avoid biased interpretation. This review presents an overview of existing population studies, challenges, and potential solutions to facilitate future population analyses.

Baptista, Rodrigo P.; Cooper, Garrett W.; Kissinger, Jessica C. 2021. Genes 12, no. 6: 894. https://doi.org/10.3390/genes12060894

A novel fragmented mitochondrial genome in the protist pathogen Toxoplasma gondii and related tissue coccidia

Donna Huber on April 27, 2021

Mitochondrial genome content and structure vary widely across the eukaryotic tree of life, with protists displaying extreme examples. Apicomplexan and dinoflagellate protists have evolved highly reduced mitochondrial genome sequences, mtDNA, consisting of only three cytochrome genes and fragmented rRNA genes. Here, we report the independent evolution of fragmented cytochrome genes in Toxoplasma and related tissue coccidia and evolution of a novel genome architecture consisting minimally of 21 sequence blocks (SBs) totaling 5.9 kb that exist as nonrandom concatemers. Single-molecule Nanopore reads consisting entirely of SBs ranging from 0.1 to 23.6 kb reveal both whole and fragmented cytochrome genes. Full-length cytochrome transcripts including a divergent coxIII are detected. The topology of the mitochondrial genome remains an enigma. Analysis of a cob point mutation reveals that homoplasmy of SBs is maintained. Tissue coccidia are important pathogens of man and animals, and the mitochondrion represents an important therapeutic target. The mtDNA sequence has been elucidated, but a definitive genome architecture remains elusive.

Sivaranjani Namasivayam, Rodrigo P Baptista, Wenyuan Xiao, Erica M Hall, Joseph S Doggett, Karin Troell, Jessica C Kissinger. Genome Res. 2021 May;31(5):852-865. doi: 10.1101/gr.266403.120.

Strain-specific genome evolution in Trypanosoma cruzi, the agent of Chagas disease

Donna Huber on January 28, 2021

The protozoan Trypanosoma cruzi almost invariably establishes life-long infections in humans and other mammals, despite the development of potent host immune responses that constrain parasite numbers. The consistent, decades-long persistence of T. cruzi in human hosts arises at least in part from the remarkable level of genetic diversity in multiple families of genes encoding the primary target antigens of anti-parasite immune responses. However, the highly repetitive nature of the genome-largely a result of these same extensive families of genes-have prevented a full understanding of the extent of gene diversity and its maintenance in T. cruzi. In this study, we have combined long-read sequencing and proximity ligation mapping to generate very high-quality assemblies of two T. cruzi strains representing the apparent ancestral lineages of the species. These assemblies reveal not only the full repertoire of the members of large gene families in the two strains, demonstrating extreme diversity within and between isolates, but also provide evidence of the processes that generate and maintain that diversity, including extensive gene amplification, dispersion of copies throughout the genome and diversification via recombination and in situ mutations. Gene amplification events also yield significant copy number variations in a substantial number of genes presumably not required for or involved in immune evasion, thus forming a second level of strain-dependent variation in this species. The extreme genome flexibility evident in T. cruzi also appears to create unique challenges with respect to preserving core genome functions and gene expression that sets this species apart from related kinetoplastids.

Wang W, Peng D, Baptista RP, Li Y, Kissinger JC, Tarleton RL (2021) Strain-specific genome evolution in Trypanosoma cruzi, the agent of Chagas disease. PLoS Pathog 17(1): e1009254. https://doi.org/10.1371/journal.ppat.1009254

Analysis of Long Non-Coding RNA in Cryptosporidium parvum Reveals Significant Stage-Specific Antisense Transcription

Donna Huber on January 14, 2021

Cryptosporidium is a protist parasite that has been identified as the second leading cause of moderate to severe diarrhea in children younger than two and a significant cause of mortality worldwide. Cryptosporidium has a complex, obligate, intracellular but extra cytoplasmic lifecycle in a single host. How genes are regulated in this parasite remains largely unknown. Long non-coding RNAs (lncRNAs) play critical regulatory roles, including gene expression across a broad range of organisms. Cryptosporidium lncRNAs have been reported to enter the host cell nucleus and affect the host response. However, no systematic study of lncRNAs in Cryptosporidium has been conducted to identify additional lncRNAs. In this study, we analyzed a C. parvum in vitro strand-specific RNA-seq developmental time series covering both asexual and sexual stages to identify lncRNAs associated with parasite development. In total, we identified 396 novel lncRNAs, mostly antisense, with 86% being differentially expressed. Surprisingly, nearly 10% of annotated mRNAs have an antisense transcript. lncRNAs occur most often at the 3′ end of their corresponding sense mRNA. Putative lncRNA regulatory regions were identified and many appear to encode bidirectional promoters. A positive correlation between lncRNA and upstream mRNA expression was observed. Evolutionary conservation and expression of lncRNA candidates was observed between C. parvum, C. hominis and C. baileyi. Ten C. parvum protein-encoding genes with antisense transcripts have P. falciparum orthologs that also have antisense transcripts. Three C. parvum lncRNAs with exceptional properties (e.g., intron splicing) were experimentally validated using RT-PCR and RT-qPCR. This initial characterization of the C. parvum non-coding transcriptome facilitates further investigations into the roles of lncRNAs in parasite development and host-pathogen interactions.

Yiran Li, Rodrigo P. Baptista, Adam Sateriale, Boris Striepen and Jessica C. Kissinger. Front Cell Infect Microbiol. 2021 Jan 14;10:608298. doi: 10.3389/fcimb.2020.608298. eCollection 2020.

Jessica Kissinger elected ASTMH Fellow

Donna Huber on November 16, 2020

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.”

Resistance to some, but not other dimeric lindenane sesquiterpenoid esters is mediated by mutations in a Plasmodium falciparum esterase

Donna Huber on September 24, 2020

Unique lindenane sesquiterpenoid dimers from Chloranthecae spp. were recently identified with promising in vitro antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, in vitro selection of Plasmodium falciparum resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored. In all selected resistant clones, the half-maximal effective concentration (EC50) of chlorajaponilide C increased >250-fold, and whole genome sequencing revealed mutations in the recently discovered P. falciparum prodrug activation and resistance esterase (PfPARE). Chlorajaponilide C was highly potent (mean EC50 = 1.6 nM, n=34) against fresh Ugandan P. falciparum isolates. Analysis of the structure-resistance relationships revealed that in vitro potency of a subset of lindenane sesquiterpenoid dimers was not mediated by PfPARE mutations. Thus, chlorajaponilide C, but not some related compounds, required parasite esterase activity for in vitro potency, and those compounds serve as the foundation for development of potent and selective antimalarials.

Joshua H Butler, Rodrigo P Baptista, Ana Lisa Valenciano, Bin Zhou, Jessica C Kissinger, Patrick K Tumwebaze, Philip J Rosenthal, Roland Cooper, Jian-Min Yue, Maria Belen Cassera. ACS Infect Dis. 2020 Sep 24. doi: 10.1021/acsinfecdis.0c00487

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