The African trypanosome parasite uses a genetic "cloaking device" to evade the human immune system, and researchers are now systematically decoding the genes that control this and other deadly tricks. Sleeping sickness, caused by the single-celled parasite *Trypanosoma brucei*, kills thousands of people in sub-Saharan Africa each year, while the livestock form, Nagana, devastates rural economies. Despite decades of study, the molecular machinery behind the parasite's virulence—how it switches its surface coat to avoid immune attack, senses when to prepare for transmission to a new host, and resists drugs—has remained largely unknown. This project uses a high-throughput genetic screening technique called RIT-seq to identify every gene involved in these processes. If successful, the work will reveal exactly how existing drugs kill the parasite and, critically, how resistance might emerge. It will also uncover the genetic basis of antigenic variation, the parasite's shape-shifting defence, and its ability to survive in human blood. This is fundamental science with no immediate bedside application, but understanding these core mechanisms could eventually guide the design of new drugs or vaccines. Similar genetic decoding in other parasites has already opened unexpected avenues for treating malaria and leishmaniasis.
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The African trypanosome, Trypanosoma brucei, is transmitted among mammalian hosts by the tsetse fly. These protozoan parasites cause Human African Trypanosomiasis, or sleeping sickness, and the livestock disease, Nagana. Unfortunately, molecular mechanisms affecting virulence, antigenic variation, transmission, drug susceptibility and human serum susceptibility have remained largely unknown. We have developed RNA interference (RNAi) library screening for exploitation of T. brucei genome sequence data. The power of the RNAi target sequencing (RIT-seq) approach was recently demonstrated by our high throughput decoding of drug efficacy and resistance mechanisms (Alsford et al., 2012. Nature. 482:232-6). I now propose to use RIT-seq to decode the genetic basis of fundamental aspects of T. brucei biology and pathogenesis. The key goals are to characterize the machineries that: 1. Render T. brucei susceptible to relevant drugs and inhibitors. 2. Control Variant Surface Glycoprotein gene silencing and antigenic variation. 3. Control density sensing, a pre-adaptation to host-to-host transmission. 4. Render T. brucei susceptible to lytic factors in human serum. 5. Are specifically required for survival in a mammalian host. Goal 1 has been largely achieved in terms of five drugs currently in clinical use. This demonstrates how the results reveal potential drug resistance mechanisms and present new opportunities for diagnostic and therapeutic development. We are now using T. b rucei as a model to study the action of drugs against other parasites (T. cruzi, Leishmania and Plasmodium) and have generated preliminary data for goals 2-4. We anticipate major advances in our understanding of these key virulence mechanisms.
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