African Sleeping Sickness

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Parasitic protozoa are a major cause of global infectious diseases and thus, represent one of the most serious threats to public health. Among these are African trypanosomes, the causative agents of African trypanosomiasis or sleeping sickness in humans (HAT) and a wasting and fatal disease (Nagana) in cattle, domestic pigs and other farm animals. Although the encouraging news is that HAT has been declining in recent years, livestock infections remain prevalent and have a profound effect on economic development in afflicted regions. Still, the impact of HAT is high, due to treatment costs, high morbidity and mortality and current drugs suffer from toxicity and emerging resistance. Approximately 5% of patients receiving melarsoprol die from the treatment and eflornithine is less toxic, but challenging to administer in resource-limited settings. Relapse occurs in up to 30 percent of the individuals. Nonetheless, without treatment, trypanosome infections are always fatal. Thus, further understanding of the biology of the parasite is a crucial route towards finding new therapeutic solutions for this and related diseases.

The new biology of Trypanosoma brucei: from transcriptomics to development

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Trypanosoma brucei, the causative agent of sleeping sickness, undergoes a complex life cycle between the mammalian host and the blood-feeding tsetse fly vector (Diptera: Glossinidae), which among others involves changes in cell morphology, metabolism, signaling pathways and gene expression. Consequently, these parasites have evolved adaptations to allow for their survival in both the gut and salivary glands of the tsetse fly, as well as in the bloodstream of their mammalian host. One of the fundamental steps in the life of a pathogen is the acquisition of infectivity. In the case of African trypanosomes, this occurs in the tsetse fly. Although the intricate nature of trypanosome development in the fly has been recognized for more than a century, the molecular mechanisms are still mysterious, due to experimental challenges of studying parasites in the fly. By analyzing the transcriptome of trypanosomes derived from infected tsetse flies, we have recently succeeded in reproducing in the laboratory the developmental stages found in the insect vector, including the generation of infective metacyclics expressing the variant surface glycoprotein (VSG) coat. This experimental system has the potential to contribute towards developing new intervention strategies, including transmission blocking vaccines, which are currently being sought in other arthoropod-transmitted diseases as alternatives to conventional vaccines against pathogens.

Mining genomic information to expose new strategies to combat the diseases caused by African trypanosomes and related parasites

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Identifying genes essential for survival in the host is fundamental toward unraveling the biology of human pathogens and understanding mechanisms of pathogenesis. Recent advances in genomics research are providing new avenues to a more holistic understanding of pathogens. We are using next-generation sequencing technologies and high-throughput proteomics to determine the coding capacity of the T. brucei and Leishmania braziliensis genomes and to expose gene expression landscapes that parasites use to adapt to different environments in their life cycle.

Publications

Kolev NG, Ullu E and Tschudi C: The emerging role of RNA-binding proteins in the life cycle of Trypanosoma brucei. Cell Microbiol. 2014 Apr;16 (4) :482-9. Epub 2014 Feb 16. PMID: 24438230


Ericson M, Janes MA, Butter F, Mann M, Ullu E and Tschudi C: On the extent and role of the small proteome in the parasitic eukaryote Trypanosoma brucei. BMC Biol. 2014 Feb 19;12 :14. Epub 2014 Feb 19. PMID: 24552149


Shi H, Barnes RL, Carriero N, Atayde VD, Tschudi C and Ullu E: Role of the Trypanosoma brucei HEN1 family methyltransferase in small interfering RNA modification. Eukaryot Cell. 2014 Jan;13 (1) :77-86. Epub 2013 Nov 1. PMID: 24186950

Atayde VD, Shi H, Franklin JB, Carriero N, Notton T, Lye LF, Owens K, Beverley SM, Tschudi C and Ullu E: The structure and repertoire of small interfering RNAs in Leishmania (Viannia) braziliensis reveal diversification in the trypanosomatid RNAi pathway. Mol Microbiol. 2013 Feb;87 (3) :580-93. Epub 2012 Dec 26. PMID: 23217017

Kolev NG, Ramey-Butler K, Cross GA, Ullu E and Tschudi C: Developmental progression to infectivity in Trypanosoma brucei triggered by an RNA-binding protein. Science. 2012 Dec 7;338 (6112) :1352-3. PMID: 23224556


Tschudi C, Shi H, Franklin JB and Ullu E: Small interfering RNA-producing loci in the ancient parasitic eukaryote Trypanosoma brucei. BMC Genomics. 2012 Aug 27;13 :427. Epub 2012 Aug 27. PMID: 22925482


Barnes RL, Shi H, Kolev NG, Tschudi C and Ullu E: Comparative genomics reveals two novel RNAi factors in Trypanosoma brucei and provides insight into the core machinery. PLoS Pathog. 2012;8 (5) :e1002678. Epub 2012 May 24. PMID: 22654659

Kolev NG, Tschudi C and Ullu E: RNA interference in protozoan parasites: achievements and challenges. Eukaryot Cell. 2011 Sep;10 (9) :1156-63. Epub 2011 Jul 15. PMID: 21764910


Atayde VD, Tschudi C and Ullu E: The emerging world of small silencing RNAs in protozoan parasites. Trends Parasitol. 2011 Jul;27 (7) :321-7. Epub 2011 Apr 15. PMID: 21497553

Lye LF, Owens K, Shi H, Murta SM, Vieira AC, Turco SJ, Tschudi C, Ullu E and Beverley SM: Retention and loss of RNA interference pathways in trypanosomatid protozoans. PLoS Pathog. 2010 Oct 28;6 (10) :e1001161. Epub 2010 Oct 28. PMID: 21060810


Kolev NG, Franklin JB, Carmi S, Shi H, Michaeli S and Tschudi C: The transcriptome of the human pathogen Trypanosoma brucei at single-nucleotide resolution. PLoS Pathog. 2010 Sep 9;6 (9) :e1001090. Epub 2010 Sep 9. PMID: 20838601

Shi H, Chamond N, Djikeng A, Tschudi C and Ullu E: RNA interference in Trypanosoma brucei: role of the n-terminal RGG domain and the polyribosome association of argonaute. J Biol Chem. 2009 Dec 25;284 (52) :36511-20. Epub 2009 Oct 30. PMID: 19880512