When he first heard about the African protozoa that cause sleeping sickness, Keith Matthews was hooked. “I heard a lecture as an undergraduate on trypanosomes,” he said, “and thought it sounded really fascinating.”
He wrote to potential graduate school supervisors, eventually enrolling at the University of Glasgow to study how the parasite evades the host’s immune response.
After obtaining his doctorate, Matthews moved to Yale University on a NATO scholarship, then to the University of Manchester before transferring his laboratory to the University of Edinburgh, to study the trypanosome life cycle.
“Innovative and groundbreaking research is a hallmark of Keith’s research group,” former mentor Christian Tschudi wrote in his letter supporting Matthews’ nomination for the American Society’s Alice and CC Wang Prize in Molecular Parasitology. for Biochemistry and Molecular Biology. Matthews will receive the award at Discover BMB 2023 in Seattle.
Such work does not come out of nowhere. Matthews has established a lab environment where members feel free to innovate and help each other. “It depends on the people in the lab and their willingness to help each other,” he said. “Many breakthroughs have been the direct result of Ph.D. student work in the lab.
He also makes mentoring a priority. “Nobody is doing their best,” he said. “You have to be constructive and help keep them excited.”
And he’s still looking for answers about trypanosomes like he was as an undergrad. “There are searches where I still have no idea what the results are telling us,” he said.
Although it can be frustrating, there is an upside: “We are lucky in parasitology; there are so many interesting questions out there. Ultimately, we seek the truth. It’s that simple.”
How a trypanosome knows it’s time to change
Transmitted by tsetse flies, trypanosomes infect mammals, including humans and cattle, causing trypanosomiasis or sleeping sickness. Keith Matthews studied how the life cycle of protozoa in mammals and flies is regulated and how the parasite controls its growth and infectivity.
Trypanosomes replicate in the host’s bloodstream in what is called their ‘slender form’. But to successfully transfer to the tsetse fly, they must be in their “stumpy form”, in which they stop dividing. Matthews’ lab strives to explain how and why this change occurs.
The team first used an RNAi screen to identify signaling in the trypanosome that tells it to switch to the stumpy form. Then they went up the path and looked for the external signal that triggers the waterfall.
“In a way, we did it backwards,” Matthews said.
They identified the parasite quorum-sensing mechanism, or the communication that there are enough of them in the host’s blood to be transmitted by the fly and that it’s time to prepare.
The lab found that peptidases released by trypanosomes cleave host proteins, releasing small oligopeptides. When a high enough concentration of parasites are in the bloodstream, these oligopeptides are at a correspondingly high level and are transported by a molecule to the surface of the parasite, triggering the signaling cascade and transforming the slender forms into chunky ones, ready to live in the tsetse. fly.