African Sleeping Sickness

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

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

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

Chikne V, Gupta SK, Doniger T, K SR, Cohen-Chalamish S, Ben-Asher HW, Kolet L, Yahia NH, Unger R, Ullu E, Kolev NG, Tschudi C, Michaeli S: The Canonical Poly (A) Polymerase PAP1 Polyadenylates Non-Coding RNAs and Is Essential for snoRNA Biogenesis in Trypanosoma brucei. J Mol Biol. 2017 Oct 27; 2017 Apr 26. PMID: 28456523

Christiano R, Kolev NG, Shi H, Ullu E, Walther TC, Tschudi C: The proteome and transcriptome of the infectious metacyclic form of Trypanosoma brucei define quiescent cells primed for mammalian invasion. Mol Microbiol. 2017 Oct; 2017 Aug 4. PMID: 28742275

Kolev NG, Günzl A, Tschudi C: Metacyclic VSG expression site promoters are recognized by the same general transcription factor that is required for RNA polymerase I transcription of bloodstream expression sites. Mol Biochem Parasitol. 2017 Sep; 2017 Jul 14. PMID: 28716719

Damasceno JD, Silva G, Tschudi C, Tosi LR: Evidence for regulated expression of Telomeric Repeat-containing RNAs (TERRA) in parasitic trypanosomatids. Mem Inst Oswaldo Cruz. 2017 Aug. PMID: 28767983

Savage AF, Kolev NG, Franklin JB, Vigneron A, Aksoy S, Tschudi C: Transcriptome Profiling of Trypanosoma brucei Development in the Tsetse Fly Vector Glossina morsitans. PLoS One. 2016; 2016 Dec 21. PMID: 28002435

Chikne V, Doniger T, Rajan KS, Bartok O, Eliaz D, Cohen-Chalamish S, Tschudi C, Unger R, Hashem Y, Kadener S, Michaeli S: A pseudouridylation switch in rRNA is implicated in ribosome function during the life cycle of Trypanosoma brucei. Sci Rep. 2016 May 4; 2016 May 4. PMID: 27142987

Ramey-Butler K, Ullu E, Kolev NG, Tschudi C: Synchronous expression of individual metacyclic variant surface glycoprotein genes in Trypanosoma brucei. Mol Biochem Parasitol. 2015 Mar-Apr; 2015 Apr 18. PMID: 25896436

Kolev NG, Ullu E, Tschudi C: Construction of Trypanosoma brucei Illumina RNA-Seq libraries enriched for transcript ends. Methods Mol Biol. 2015. PMID: 25388113

Eliaz D, Doniger T, Tkacz ID, Biswas VK, Gupta SK, Kolev NG, Unger R, Ullu E, Tschudi C, Michaeli S: Genome-wide analysis of small nucleolar RNAs of Leishmania major reveals a rich repertoire of RNAs involved in modification and processing of rRNA. RNA Biol. 2015; 2015 May 13. PMID: 25970223

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

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

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