Infections, Immunity and Microbes
 

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Bill Wickstead

Associate Professor, Faculty of Medicine & Health Sciences

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Research Summary

My research interests include genome architecture, chromosome segregation, molecular motor function and multigene-family evolution. The uniting factor behind these topics is the importance they have… read more

Recent Publications

Current Research

My research interests include genome architecture, chromosome segregation, molecular motor function and multigene-family evolution. The uniting factor behind these topics is the importance they have to understanding the biology of the parasite Trypanosoma brucei. Much of the research in the lab also integrates bioinformatic and mathematical tools with wet-bench work. The use of these tools - particularly in an age where so much genomic information is becoming available - can greatly speed-up biological research and help us to ask the right questions of the systems we study.

More information regarding the lab's research can be found at: www.wicksteadlab.co.uk.

African trypanosomes and antigenic variation

Trypanosoma brucei is a single-celled parasite of the blood which causes the disease "sleeping sickness" in humans. The disease kills ~50 000 annually in sub-Saharan regions and has been identified by the World Health Organisation as a neglected tropical disease. A related disease of cattle, n'gana, also has a major detrimental economic impact in some of Africa's poorest regions. The parasite is transmitted by the bite of the tsetse fly, and is unusual in parasitizing the bloodstream in an exclusively extracellular form - effectively in full view of the immune system. This feat is achieved by the parasite expressing a series of immunologically-distinct cell surface coats - a process known as antigenic variation. Trypanosome antigenic variation is an extreme version of a strategy of immune evasion used by a great number of parasites and pathogens (including malaria parasites, Giardia, Borrelia, Neisseria, and HIV), and understanding how trypanosomes achieve it is relevant to understanding other diseases as well as sleeping sickness itself.

Trypanosome antigenic variation

Genome architecture and segregation

The genome of T. brucei is highly adapted to the organism's lifestyle; around 20% of the entire genome sequence is dedicated to the process of antigenic variation. This includes a large number (~100) of linear minichromosomes, which serve as a reservoir for genes encoding cell surface proteins. At cell division, all of these chromosomes are segregated by the mitotic spindle with great fidelity. However, the chromosomes far out-number the spindle microtubules and the molecular details of this segregation mechanism are almost entirely unknown. The lab is currently working to discover the components of the mitotic machinery in trypanosomes and what features of the small chromosomes enable them to interact with the spindle. This will reveal how an essential part of the trypanosome cell functions and will also tell us about the evolution of mitosis in other organisms.

T.brucei karyotype

Molecular motors

The mitotic spindle is a specific part of the wider cytoskeleton - a system of filaments and molecular motors that is crucial for cell shape, division, movement and growth. There are three major classes of motor protein that move on the cytoskeleton of eukaryotes (that is, more complex non-bacterial organisms) - myosins, kinesins and dyneins. Only kinesins have thus-far been seen to be ubiquitously present in all eukaryotes, with losses of either all myosins or all dyneins from particular branches of the eukaryotic tree. All three motor classes are superfamilies of proteins encompassing multiple types with specific functions. The lab has worked extensively to characterize the types of motor found in cells and in this way has discovered "new" families of motors for which little functional data are available. Work in the lab is characterizing these families and also testing the function of unclassified motors in trypanosome growth and division.

Kinesin13 localisation

Evolution of the cell

Trypanosomes are unlike model organisms like yeast in several key ways. However, trypanosomes share a common ancestor with all other eukaryotes and the features of this lineage evolved from the same ancestral cell. With the advent of genome sequencing for increasing numbers of eukaryotes, it is becoming possible to compare the complete content of multiple organisms. In this way, we can make predictions about the functions performed by a specific organism, even when that function has not been directly observed. Moreover, by inferring the genomic content of the ancestors to particular lineages, it is possible to look back in time to "observe" long extinct cells in terms of their encoded biology. The lab is using these comparative genomic methods to reconstruct the evolution of key features of eukaryotic cells.

LECA

Infections, Immunity and Microbes

School of Life Sciences
University of Nottingham
Medical School
Queen's Medical Centre
Nottingham NG7 2UH