Parasitic Diseases; Genomics
Unraveling the biology of pathogens is fundamental toward understanding mechanisms of pathogenesis and identifying genes essential for survival in the host. Our research focuses on the protozoan parasite Trypanosoma brucei, which causes devastating diseases in humans and animals in sub-Saharan Africa. We are applying RNA interference (RNAi), namely down-regulation of gene expression by homologous double-stranded RNA, to identify genes essential for survival within the insect vector and mammalian host. In addition, high-throughput next-generation sequencing technologies (RNA-Seq) are used to analyze gene expression patterns (the transcriptome) during the developmental cycle. Lastly, we are interested in understanding gene silencing by RNAi in African trypanosomes with the objective to uncover its biological function.
Extensive Research Description
Professor Tschudi’s studies focus on the biology of trypanosomes the
causative agents of devastating diseases in Africa and South America.
Most projects in the laboratory utilize bioinformatics and modern
genetic techniques to identify and dissect parasite-specific functions.
The laboratory has developed several methodologies for creating mutants
and has been instrumental in establishing a number of techniques to
study processes at the biochemical level. These approaches will lead to
a better understanding of the infectious cycle of the parasite, which
involves a mammalian as well as an insect host. The long term goal is
to identify candidate molecules that can be targets for chemotherapy.
Most recently, we have established and used RNA-sequencing (RNA-Seq), a novel high-throughput sequencing technology, to interrogate the transcriptome of the parasitic protozoa Trypanosoma brucei, the agent of African sleeping sickness in man and nagana in cattle. In the course of this work, we have optimized the RNA-Seq protocol for use with trypanosomatids, built our own server, implemented a stream-lined bioinformatics pipeline and generated one of the most comprehensive genome-wide transcript maps at single-nucleotide resolution. Such information is central to the identification of functional elements, to determine the timing and regulation of gene expression in different developmental stages and to identify novel drug targets. Indeed, this work has dramatically expanded the repertoire of known genes to include over 1,000 novel genes with many displaying features suggesting that they are secreted or modulate the characteristics of membranes and thus play a role in the response of T. brucei to the changing environment during its complex life cycle. We recently expanded the transcriptome studies to developmental stages of T. brucei in the tsetse fly vector (in collaboration with Dr. Aksoy) and to the life cycle of Leishmania (Viannia) panamensis (in collaboration with Dr. McMahon-Pratt).
- Profiling the transcriptome of the parasitic protozoa Trypanosoma brucei, the agent of African sleeping sickness in man and nagana in cattle, by next-generation high-throughput sequencing.
- Characterization of molecular mechanisms Involved in RNA metabolism with special emphasis on RNA interference and the role of small RNAs in trypanosome biology, a collaboration with Professor Elisabetta Ullu at Yale University
- Developmental biology of African trypanosomes in its Invertebrate Host, a collaborative effort with Professor Serap Aksoy in the Department of Epidemiology of Microbial Diseases
- Characterization of enzymes involved in RNA modification, a collaboration with Professor Shulamit Michaeli at Bar Ilan University in Tel Aviv, Israel
- Kolev, N.G., Ramey-Butler, K., Cross, G.A., Ullu, E., and Tschudi, C. (2012) Developmental progression to infectivity in Trypanosoma brucei triggered by an RNA-binding protein. Science 338(6112):1352-1353.
- Barnes, R.L., Shi, H., Kolev, N.G., Tschudi, C. and Ullu E. (2012) Comparative genomics reveals two novel RNAi factors in Trypanosoma brucei and provides insight into the core machinery PLoS Pathog 8(5): e1002678. doi:10.1371/journal.ppat.1002678.
- Kolev, N.G., Franklin, J.B., Carmi, S., Shi, H., Michaeli, S. and Tschudi, C. (2010). The transcriptome of the human pathogen Trypanosoma brucei at single-nucleotide resolution. PLoS Pathog., 6(9): e1001090. doi:10.1371/journal.ppat.1001090.
- Lye, L.F., Owens, K., Shi, H., Murta, S.M., Vieira, A.C., Turco, S.J., Tschudi, C., Ullu, E. and Beverley, S.M. (2010). Retention and loss of RNA interference pathways in trypanosomatid protozoans. PLoS Pathog., 6(10): e1001161. doi:10.1371/journal.ppat.1
- Patrick, K.L, Shi, H., Kolev, N.G., Ersfeld, K., Tschudi, C. and Ullu, E. (2009). Distinct and overlapping roles for two Dicer-like proteins in the RNA interference pathways of the ancient eukaryote Trypanosoma brucei. Proc. Natl. Acad. Sci. U S A, 106, 1
- Arhin, G.K., Li, H., Ullu, E., and Tschudi, C. (2006). A protein related the vaccinia virus cap-specific methyltransferase VP39 is involved in cap 4 modification in Trypanosoma brucei. RNA 12:53-62.