Keith Matthews

Background

1986-1990    PhD studentship; University of Glasgow.

1990-1992    NATO Post doctoral Fellowship, Yale University, U.S.A.

1992-1995    Wellcome Trust Postdoctoral Fellow, University of Manchester.

1996-2001    Dunkerly Research Fellowship in Biochemistry, University of Manchester.

2001-2003    Wellcome Trust University Award recipient, University of Manchester.

2003-2004    Senior Lecturer, University of Manchester.

2004-2007    Reader in Parasite Biology, University of Edinburgh.

2007-present    Professor of Parasite Biology, University of Edinburgh.

2011-present    Director, Centre for Immunity, Infection and Evolution

Research summary

http://matthews.bio.ed.ac.uk/

African trypanosomes are parasites that have immense economic impact in sub Saharan Africa. They infect game and domestic animals (in which they cause the disease nagana) as well as humans (where they cause sleeping sickness). The parasites are transmitted by tsetse flies. Our lab focuses on the changes that take place in the parasite as it prepares for, and adapts to, life in the tsetse fly. In the bloodstream, the parasites communicate with one another via a quorum sensing-like process to optimise transmission. In the tsetse fly, differentiation involves integrated changes in parasite metabolism, morphology, surface antigen expression and cell cycle progression. Using research approaches that integrate molecular cell biology, targeted reverse genetic approaches, global RNA and protein analysis, genome-wide RNAi screens and basic parasite biology we are dissecting in detail the biology of trypanosome transmission and its effects on trypanosome virulence and disease spread.

•    By in vivo and in vitro selection schemes we have generated parasite lines which cannot differentiate either in the bloodstream or when entering the tsetse fly (this development being mimicked in vitro). Key molecules required for perception of the signal to differentiate in both the bloodstream and tsetse midgut have been identified and their interactions and signalling pathways are under study.

•    Cytological analysis of differentiation defective cell lines has told us that transmission competence in trypanosomes is dependent upon a developmental event that occurs in the mammalian bloodstream: the generation of stumpy forms. The basis of transmission competence in stumpy forms is under study as are the molecular determinants that prolong stumpy survival in the bloodstream and tsetse midgut.

•    We have discovered regulatory RNA binding proteins that control parasite development- both in the bloodstream and in the tsetse fly. The function of these molecules is being investigated through analyses of their molecular interactions with RNA and other proteins.

•    Signalling events implicated in controlling differentiation are being investigated and the parasite’s mechanisms of environmental sensing and parasite-parasite communication being assembled. This exploits our discovery of a protein tyrosine phosphatase and downstream signalling pathway components that govern differentiation in the tsetse and regulators of quorum sensing in the bloodstream, discovered in a comprehensive genome-wide RNAi screen.

These studies are providing insight into how trypanosomes regulate their virulence and transmission competence. Further, the alternation between cell proliferation and development characteristic of trypanosomes is common to most protozoan parasites of global health importance (jncluding malaria, T. cruzi, Leishmania spp. etc.) such that our findings have fundamental relevance to many pathogens of humans and animals, providing new opportunities for both therapy and diagnosis.

Research activities

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