Trypanosoma brucei is transmitted by the Tsetse fly in sub-Saharan Africa and is the causative agent of Human African Trypanosomiasis, also known as Sleeping Sickness, which is responsible for a considerable disease burden and loss of life. T. brucei also causes Nagana, a corresponding disease in livestock, which creates a barrier to agricultural and economic progress in the areas it is endemic. Control of this disease is tenuous, at best, due to a lack of safe, effective, and easily administered treatment options. Additionally, due to increasing drug resistance, there is concern that re-emergence of the disease may occur, as has happened in the past. It is therefore imperative that additional understanding of this parasite be gained. T. brucei has evolved numerous immune evasion techniques that make it well suited to its various mammalian hosts, most notable of which is its ability of antigenic variation. In the mammalian bloodstream, T. brucei is completely covered by a dense coat of variant surface glycoprotein (VSG) that is expressed from a single gene drawn from a large gene family. Antigenic variation is achieved by periodically switching to the expression of a different VSG gene, which results in a new parasite population which escapes detection by the immune system. Moreover, VSG expression is essential for parasite viability even in the absence of immunological forces (i.e. in culture). The main goal of this project is to study the specific function of the essential subunit 2 of class I transcription factor A (CITFA) tht is absolutely required for VSG transcription. Preliminary data indicates that CITFA-2 directly contacts the promoter and is less abundant than other CITFA subunits, suggesting that it plays a key role in regulating monoallelic VSG expression. Additionally, CITFA-2 inclusion appears to define the active CITFA complex. CITFA-2 can therefore be used as a tool for isolation and identification of proteins which associate specifically with active CITFA.
Trypanosomes and other related parasites cause a significant amount of suffering and death around the world, usually in areas where people are poorest and most vulnerable. Unfortunately, very few treatments exist to combat these infections, and most are problematic or ineffective. Through studying the essential protein CITFA-2, we hope to gain a better understanding of how these parasites function, particularly in regard to their main immune evasion mechanism, with a special interest in finding parasite molecules which could be targeted by new drugs.
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|Kirkham, Justin K; Park, Sung Hee; Nguyen, Tu N et al. (2016) Dynein Light Chain LC8 Is Required for RNA Polymerase I-Mediated Transcription in Trypanosoma brucei, Facilitating Assembly and Promoter Binding of Class I Transcription Factor A. Mol Cell Biol 36:95-107|
|Günzl, Arthur; Kirkham, Justin K; Nguyen, Tu N et al. (2015) Mono-allelic VSG expression by RNA polymerase I in Trypanosoma brucei: expression site control from both ends? Gene 556:68-73|