A silent killer, a genome in flux: understanding the adaptive consequences of plody instability in the parasite Trypanosoma cruzi.
Supervisor: Professor Martin Llewellyn, School of Biodiversity, One Health and Veterinary Medicine
Chagas disease is the most important parasitic in Latin America, killing 12,000 people every year. To provide context, malaria in the region kills a fraction of that number (200-400 annually). Infection with T. cruzi in Chagas disease patients is life-long. Drug treatments are limited, often ineffective at clearing parasite infection, and almost always ineffective at alleviating debilitating chronic symptoms (heart disease, GI tract abnormalities). Despite the impact of Chagas disease on human health, relatively little is known about its biology by comparison to other related human parasites - T. brucei (agent of sleeping sickness) and Leishmania (agent of Leishmaniasis). Important knowledge gaps exist around how T. cruzi adapts to environmental stressors. Addressing theses gaps could shed light on how the parasite avoids host immunity to establish persistent infections in its host, as well as how it survives drug treatment.
DNA sequencing of T. cruzi isolates by members in our lab reveals a genome in a constant state of re-arrangement. The number, sizes, copy number and composition of T. cruzi chromosomes can vary substantially between closely related isolates, as well as, based on pilot data, from individual human infections sampled at different time points. The adaptive value of such genomic re-arrangements may hold the key to understanding, and addressing, many intractable aspects of T. cruzi biology. In this proposal we leverage advances in genomics, genetic manipulation, animal disease models, as well as a world-class research team to understand how T. cruzi genomic re-arrangements may underpin long term survival in the mammalian host as well as parasite resistance to frontline and next generation drugs. Using single cell genomics, wel link genomic re-arrangements to drug resistance and then, via genetic manipulation, attempt to interrupt the machinery that enables such re-arrangements to occur.