Scientists at the Yale School of Public Health and Yale School of Medicine have for the first time replicated in a laboratory setting the process of becoming infectious that occurs in the parasite that causes trypanosomiasis, more commonly known as African sleeping sickness.
The accomplishment, which researchers hail as a breakthrough, could lead to a better understanding of the molecular mechanisms by which the pathogen acquires infectivity and might eventually result in studies that block the transmission of the disease.
For the first time scientists will be able to replicate and study the development of infectivity outside the tsetse fly vector. Previously, the pathogen had to be propagated in the fly and extracted, a cumbersome and expensive procedure.
Trypanosoma brucei, the parasite responsible for the deadly disease that afflicts thousands of people in rural regions of sub-Saharan Africa, undergoes a complex life cycle between the mammalian host and the blood-feeding tsetse fly. The significance of the tsetse fly vector in transmission of African trypanosomes was first documented over a century ago, but many aspects of trypanosome biology in the insect vector remain shrouded in mystery. In particular, there is limited knowledge of the molecular mechanisms underlying the complex processes trypanosomes undergo during their journey through the tsetse fly. For example, trypanosomes lose their ability to infect mammals soon after a tsetse fly takes a blood meal on an infected host, but regain infectivity once they migrate to the salivary glands. The main difficulties in investigating these stages of the life cycle have been the absence of in vitro culture conditions and experimental challenges of studying parasites in the fly.
Yale scientists and colleagues from Rockefeller University discovered that by overexpressing an RNA-binding protein known as RBP6 in cultured non-infectious cells, they triggered a previously unknown cascade of events leading to infection of the parasite. Molecules like RBP6 have been postulated to regulate gene expression in trypanosomes, but this is the first study to identify a master regulator.
“Serendipity happens in science,” says lead researcher, Christian Tschudi, Ph.D., professor in the Department of Epidemiology of Microbial Diseases, who confesses that he didn’t believe the result the first time it happened. “This completely unexpected and unbelievable outcome made us realize that we now have a handle on a stage of the parasite life cycle that has been referred to as the ‘heart of darkness.’ If we figure out how the parasite becomes infectious, we might be able to intervene with this crucial step of its life cycle.”
The discovery grew out of a collaboration between the labs of Tschudi and Serap Aksoy, Ph.D., also a YSPH professor in the Department of Epidemiology of Microbial Diseases. Aksoy’s group maintains one of two colonies of tsetse flies in the United States.
The in vitro process opens numerous avenues of research that will, among others, result in a detailed understanding how the pathogen becomes infectious and, further down the road, will provide an opening for new intervention strategies. The discovery also has implications for Nagana, a devastating livestock disease that causes an enormous economic burden in sub-Saharan Africa.
This work was reported in the December 7, 2012, issue of Science. Contributors include Nikolay Kolev, Kiantra Ramey-Butler, George Cross and Elisabetta Ullu, from the Yale and Rockefeller Universities.