Keith Matthews
Contact details
- Tel: +44 (0)131 651 3639
- Email: keith.matthews@ed.ac.uk
Address
- Street
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Rm. 460, Ashworth Building
- City
- Post code
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
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
- mSphere (Journal)
- Wellcome Trust (External organisation) to
- The Carnegie Trust for the Universities of Scotland (External organisation)
- Wellcome Trust (External organisation)
- Molecular Microbiology (Journal)
- BBSRC (External organisation)
- Gordon Research Conference to
- Molecular and Biochemical Parasitology (Journal)
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Profiling the bloodstream form and procyclic form trypanosoma brucei cell cycle using single cell transcriptomics
(74 pages)
In:
eLIFE, vol. 12
DOI: https://doi.org/10.7554/eLife.86325
Research output: Contribution to Journal › Article (Published) -
Pathogenicity and virulence of African trypanosomes: from laboratory models to clinically relevant hosts
In:
Virulence, vol. 14, pp. 1-29
DOI: https://doi.org/10.1080/21505594.2022.2150445
Research output: Contribution to Journal › Article (Published) -
Distinguishing functions of trypanosomatid protein kinases
(12 pages)
In:
Trends in Parasitology, vol. 38, pp. 950-961
DOI: https://doi.org/10.1016/j.pt.2022.08.009
Research output: Contribution to Journal › Review article (Published) -
The SPARC complex defines RNAPII promoters in Trypanosoma brucei
(23 pages)
In:
eLIFE, vol. 11
DOI: https://doi.org/10.7554/eLife.83135
Research output: Contribution to Journal › Article (Published) -
Extracellular release of two peptidases dominates generation of the trypanosome quorum-sensing signal
(14 pages)
In:
Nature Communications, vol. 13
DOI: https://doi.org/10.1038/s41467-022-31057-1
Research output: Contribution to Journal › Article (Published) -
The genomic basis of host and vector specificity in non-pathogenic trypanosomatids
(22 pages)
In:
Biology Open, vol. 11
DOI: https://doi.org/10.1242/bio.059237
Research output: Contribution to Journal › Article (E-pub ahead of print) -
Comparative sensitivity and specificity of the 7SL sRNA diagnostic test for Animal Trypanosomiasis.
In:
Frontiers in Veterinary Science, vol. 9
DOI: https://doi.org/10.3389/fvets.2022.868912
Research output: Contribution to Journal › Article (Published) -
Comment on 'Unexpected plasticity in the life cycle of Trypanosoma brucei'
(6 pages)
In:
eLIFE, vol. 11
DOI: https://doi.org/10.7554/eLife.74985
Research output: Contribution to Journal › Letter (Published) -
Parasite co-infection: An ecological, molecular and experimental perspective
(10 pages)
In:
Proceedings of the Royal Society B-Biological Sciences, vol. 289
DOI: https://doi.org/10.1098/rspb.2021.2155
Research output: Contribution to Journal › Article (Published) -
A systematic analysis of Trypanosoma brucei chromatin factors identifies novel protein interaction networks associated with sites of transcription initiation and termination
(17 pages)
In:
Genome Research, vol. 31, pp. 2138-2154
DOI: https://doi.org/10.1101/gr.275368.121
Research output: Contribution to Journal › Article (Published) -
Single-cell transcriptomic analysis of bloodstream Trypanosoma brucei reconstructs cell cycle progression and developmental quorum sensing
(15 pages)
In:
Nature Communications, vol. 12
DOI: https://doi.org/10.1038/s41467-021-25607-2
Research output: Contribution to Journal › Article (Published) -
Monomorphic trypanozoon: Towards reconciling phylogeny and pathologies
(10 pages)
In:
Microbial Genomics, vol. 7
DOI: https://doi.org/10.1099/mgen.0.000632
Research output: Contribution to Journal › Article (E-pub ahead of print) -
Basement membrane proteins as a substrate for efficient Trypanosoma brucei differentiation in vitro
(11 pages)
In:
PLoS Neglected Tropical Diseases, vol. 15
DOI: https://doi.org/10.1371/journal.pntd.0009284
Research output: Contribution to Journal › Article (Published) -
Application of single cell transcriptomics to kinetoplastid research
(14 pages)
In:
Parasitology, pp. 1-14
DOI: https://doi.org/10.1017/S003118202100041X
Research output: Contribution to Journal › Review article (E-pub ahead of print) -
Single cell transcriptomic analysis of bloodstream form Trypanosoma brucei reconstructs cell cycle progression and differentiation via quorum sensing
DOI: https://doi.org/10.1101/2020.12.11.420976
Research output: › Working paper (Published) -
A global analysis of low-complexity regions in the Trypanosoma brucei proteome reveals enrichment in the C-terminus of nucleic acid binding proteins providing potential targets of phosphorylation
(26 pages)
In:
Wellcome Open Research , vol. 5
DOI: https://doi.org/10.12688/wellcomeopenres.16286.2
Research output: Contribution to Journal › Article (Published) -
An atypical DYRK kinase connects quorum-sensing with posttranscriptional gene regulation in Trypanosoma brucei
In:
eLIFE, vol. 9
DOI: https://doi.org/10.7554/eLife.51620
Research output: Contribution to Journal › Article (Published) -
A leap into the unknown: Early events in African Trypanosome transmission
In:
Trends in Parasitology, vol. 36, pp. 266-278
DOI: https://doi.org/10.1016/j.pt.2019.12.011
Research output: Contribution to Journal › Review article (E-pub ahead of print) -
Developmental competence and antigen switch frequency can be uncoupled in Trypanosoma brucei
(9 pages)
In:
Proceedings of the National Academy of Sciences (PNAS), vol. 116, pp. 22774-22782
DOI: https://doi.org/10.1073/pnas.1912711116
Research output: Contribution to Journal › Article (Published) -
Quorum sensing in African Trypanosomes
In:
Current Opinion in Microbiology, vol. 52, pp. 124-129
DOI: https://doi.org/10.1016/j.mib.2019.07.001
Research output: Contribution to Journal › Review article (E-pub ahead of print)