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Tag: Jessica Kissinger

Plasmodium knowlesi Cytoadhesion Involves SICA Variant Proteins

Plasmodium knowlesi poses a health threat throughout Southeast Asian communities and currently causes most cases of malaria in Malaysia. This zoonotic parasite species has been studied in Macaca mulatta (rhesus monkeys) as a model for severe malarial infections, chronicity, and antigenic variation. The phenomenon of Plasmodium antigenic variation was first recognized during rhesus monkey infections. Plasmodium-encoded variant proteins were first discovered in this species and found to be expressed at the surface of infected erythrocytes, and then named the Schizont-Infected Cell Agglutination (SICA) antigens. SICA expression was shown to be spleen dependent, as SICA expression is lost after P. knowlesi is passaged in splenectomized rhesus. Here we present data from longitudinal P. knowlesi infections in rhesus with the most comprehensive analysis to date of clinical parameters and infected red blood cell sequestration in the vasculature of tissues from 22 organs. Based on the histopathological analysis of 22 tissue types from 11 rhesus monkeys, we show a comparative distribution of parasitized erythrocytes and the degree of margination of the infected erythrocytes with the endothelium. Interestingly, there was a significantly higher burden of parasites in the gastrointestinal tissues, and extensive margination of the parasites along the endothelium, which may help explain gastrointestinal symptoms frequently reported by patients with P. knowlesi malarial infections. Moreover, this margination was not observed in splenectomized rhesus that were infected with parasites not expressing the SICA proteins. This work provides data that directly supports the view that a subpopulation of P. knowlesi parasites cytoadheres and sequesters, likely via SICA variant antigens acting as ligands. This process is akin to the cytoadhesive function of the related variant antigen proteins, namely Erythrocyte Membrane Protein-1, expressed by Plasmodium falciparum.

Mariko S Peterson, Chester J Joyner, Stacey A Lapp, Jessica A Brady, Jennifer S Wood, Monica Cabrera-Mora, Celia L Saney, Luis L Fonseca, Wayne T Cheng, Jianlin Jiang, Stephanie R Soderberg, Mustafa V Nural, Allison Hankus, Deepa Machiah, Ebru Karpuzoglu, Jeremy D DeBarry, Rabindra Tirouvanziam, Jessica C Kissinger, Alberto Moreno, Sanjeev Gumber, Eberhard O Voit, Juan B Gutierrez, Regina Joice Cordy, Mary R Galinski. Front Cell Infect Microbiol. 2022 Jun 23;12:888496. doi: 10.3389/fcimb.2022.888496. eCollection 2022.

Small and intermediate size structural RNAs in the unicellular parasite Cryptosporidium parvum as revealed by sRNA-seq and comparative genomics

Small and intermediate-size noncoding RNAs (sRNAs and is-ncRNAs) have been shown to play important regulatory roles in the development of several eukaryotic organisms. However, they have not been thoroughly explored in Cryptosporidium parvum, an obligate zoonotic protist parasite responsible for the diarrhoeal disease cryptosporidiosis. Using Illumina sequencing of a small RNA library, a systematic identification of novel small and is-ncRNAs was performed in C. parvum excysted sporozoites. A total of 79 novel is-ncRNA candidates, including antisense, intergenic and intronic is-ncRNAs, were identified, including 7 new small nucleolar RNAs (snoRNAs). Expression of select novel is-ncRNAs was confirmed by RT-PCR. Phylogenetic conservation was analysed using covariance models (CMs) in related Cryptosporidium and apicomplexan parasite genome sequences. A potential new type of small ncRNA derived from tRNA fragments was observed. Overall, a deep profiling analysis of novel is-ncRNAs in C. parvum and related species revealed structural features and conservation of these novel is-ncRNAs. Covariance models can be used to detect is-ncRNA genes in other closely related parasites. These findings provide important new sequences for additional functional characterization of novel is-ncRNAs in the protist pathogen C. parvum.

Yiran Li, Rodrigo P Baptista, Xiaohan Mei, Jessica C Kissinger. Microb Genom. 2022 May;8(5). doi: 10.1099/mgen.0.000821

Creating databases to help cure diseases worldwide

Jessica Kissinger poses for a photo in the Infectious Diseases Institute in Uganda where she is currently a US Fullbright Scholar. (Photo/Courtesy Jessica Kissinger)

Jessica Kissinger is using her expertise in biology and big data to help other scientists

 

Jessica Kissinger never set out to make databases. From the time she was a little girl, she wanted to be a biologist.

Today, the University of Georgia professor not only studies deadly pathogens like malaria and Cryptosporidium (a waterborne parasite), but also is a driving force behind worldwide, groundbreaking collaborations on novel databases. During her time at UGA, she has received nearly $40 million in federal and private grants and contracts.

These databases can crunch vast amounts of biological information at warpspeed and reveal important patterns that pave the way for new approaches to scourges such as Leishmania (common in the tropics, subtropics, and southern Europe), toxoplasmosis (a systemic disease due to one of the world’s most common parasites), and Valley Fever (a fungus born on the wind that can cause lung and systemic infections). Novel drug and vaccine targets can be developed, as well as fresh insights on life-threatening pathogens.

“Fighting infections and developing new drug and vaccine targets requires detailed knowledge of a pathogen and how it functions,” explained Kissinger, a Distinguished Research Professor in UGA’s Department of Genetics, Institute of Bioinformatics and Center for Tropical and Emerging Global Diseases.

And, like internet searches, the databases are all free. Kissinger said it’s likely that pharmaceutical companies are mining some of the information in their quest to discover new therapeutic targets.

“They don’t tell us what they’re working on,” she said. “A database itself doesn’t produce a cure. A database can, however, remove most barriers to analysis of existing data.”

Big Data paves the way for big advances in science

It once took an entire decade to sequence a single genome—and the cost was many millions. Today, researchers can sequence a genome in a single afternoon for a few thousand dollars, transforming the field of genomics. Similar astounding advances have reshaped other ‘omics’ specialties, such as proteomics (study of proteins), metabolomics (study of metabolism), transcriptomics (study of RNA), and epigenomics (the influence of the environment on gene function). These advances mark the “Big Data” era in biology.

“The power that is unleashed by big data is phenomenal,” said Kissinger, “and it’s a very exciting time in history, with major funders and visionaries all across the world forming consortia to create a kind of ideal data universe.” Like explorers trekking into a new world, they will make discoveries we might only imagine right now.

Creating a malaria database

Kissinger’s innovations began over 23 years ago, while she was a postdoctoral researcher at the University of Pennsylvania studying a single-celled parasite called Toxoplasma gondii. The parasite shares some important features with the malaria pathogen, whose genome was in the process of being sequenced.

“I rounded up genome data from all over the world on Plasmodium (the causative agent of malaria), and ran analyses and put it on a website, so I could study the genes it might share with Toxoplasma,” she recalled. “It turns out nobody had made the Plasmodium data available for searching before.”

Soon she and her adviser, David Roos, had a million-dollar grant to formally establish a malaria database, PlasmoDB, and since its launch in 1999 it has grown to include additional pathogens and received continual funding from the NIH, the most recent for up to $38.4 million to maintain what has now become the Eukaryotic Pathogen, Vector and Host Informatics Resources knowledgebase (VEuPathDB), covering 14 different pathogens as well as host responses to infections. This comprehensive database is an integrated centralized resource for data mining on over 500 organisms.

The databases collectively contain over nine terabytes (9,000 gigabytes) of data, and have been compared to a Wikipedia for molecular parasitology by the British Society for Parasitology, which noted back in 2006: “We don’t know what we would do without it!”

Each month, VEuPathDB receives over 11 million hits from an average of 36,000 unique visitors in more than 100 countries, including India, Brazil and Kenya. A related database on vectors of disease (such as ticks that carry Lyme disease) was recently merged into VEuPathDB. The merger expanded each resource and enables researchers to better explore data on vectors such as ticks and mosquitoes and the pathogens they transmit.

Powerful tools are key to analyzing data

The databases are not just strings of numbers or words. They allow visualizations and graphic interfaces. Already, research is emerging that can help direct vaccine and drug development away from proteins that hosts and pathogens share, in order to protect the cell. Scientists using the databases have discovered proteins that reduce severe malaria and other proteins that protect malaria parasites from the human fever response. They have also found proteins that help Toxoplasma penetrate host cells.

In a single year an average of 200 publications a month cite VEuPathDB, and to date there have already been 24,000 citations total. Next up: cloud-ready applications and improved integration with yet other databases. These databases “have become essential data mining and access platforms for fungal and parasite genomics research,” said microbiologist and plant pathologist Jason Stajich of the University of California at Riverside.

“Without powerful, user-friendly tools to analyze it, “Big Data” is more a curse than a blessing,” explained John Boothroyd, an immunologist and microbiologist at Stanford University School of Medicine. “VEuPathDB is just such a tool and we owe Jessica Kissinger and her colleagues an enormous thank you for their tireless and selfless efforts to first conceive and then continuously improve this absolutely essential resource.”

Grants for related projects have come from a wide array of organizations, among them the Bill & Melinda Gates Foundation, the Sloan Foundation, and the World Health Organization. One of those projects, called ClinEpiDB, is home to a multicenter study that contains data from over 22,000 children from seven different sites in South Asia and Africa. This study is the largest ever to investigate the causes of diarrhea in children in lower- to middle-income countries. Other uses of ClinEpiDB include new data on hidden signs of malaria transmission in areas where incidence is declining, or how breastfeeding protects infants from common infections.

The VEuPathDB database would be enough to secure Kissinger’s reputation in the biological sciences, but she has not stopped there. At the University of Georgia, she was a founding member of the Institute of Bioinformatics, and served as its director from 2011 to 2109. The Institute’s mission is to facilitate cutting-edge interdisciplinary research in computational biology, and the program offers both masters and doctorates. She is a key researcher helping to partner a national hub for infectious disease research by linking with Emory University in Atlanta. The two institutions have grants totaling over $45 million to work on everything from tuberculosis to HIV to malaria.

“These databases are a success beyond my wildest dreams,” said Kissinger. “They are made by biologists for other biologists and address a real-life need.”

 

This story first appeared at UGA Today.

Jessica Kissinger elected as AAAS Fellow

Jessica Kissinger with student
Dr. Jessica Kissinger with student

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

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 knowlesiMalar 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

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. parvumCryptosporidium 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. parvumC. 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

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

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

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

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