... understanding life in molecular detail

Dr Eric Hewitt

Cell Biology, Immunology, Amyloid Disease, Natural Killer Cells


We study the cell biology of amyloid disease and the immune system

Amyloid diseases, including Alzheimer’s, Parkinsons and dialysis-related amyloidosis, are associated with the misfolding of peptides or proteins into insoluble amyloid fibrils.  Our research focuses on how these fibrils cause cellular dysfunction and cytotoxicity. In particular we are focus on how amyloid fibrils can access intracellular compartments and disrupt their function.

We are also interested in immunology with projects on the molecular basis for natural killer cell function and how viruses can evade detection by the immune system. 

Current major projects include:
  • Cell biology of amyloid disease
  • Cell biology of natural killer cells
  • Immune evasion by viruses

Cell biology of amyloid disease

Amyloid formation is associated with a spectrum of human diseases, including Alzheimer’s disease, Huntington’s disease, type II diabetes and dialysis-related amyloidosis. In these disorders proteins and peptides aggregate into insoluble amyloid fibrils and many amyloid diseases are associated with cellular dysfunction, cell death and tissue destruction. However, the identity of the culprit species and how these cause amyloid disease pathology are poorly understood.  Recent studies suggest that oligomeric intermediates are the major cytotoxic species associated with amyloid formation, leading to the notion that amyloid fibrils are an inert end product of amyloid assembly. Our data, however, demonstrate that amyloid fibrils are cytotoxic and that nanoscale fibrils produced by fragmentation exhibit greater biological activity than longer micron scale fibrils. Fibril fragmentation may therefore be a key pathological mechanism in amyloid disease.  We are investigating how these nanoscale amyloid fibrils are internalised and traffic within cells, how nanoscale amyloid fibrils interact with cellular components and how these interactions cause cellular dysfunction.

Cell biology of natural killer cells and immune evasion by viruses

Natural killer (NK) cells are specialised immune cells that eliminate infected and cancerous cells. NK cells store cytotoxic molecules (perforin and granzymes) in their secretory lysosomes. The recognition of an infected or transformed cell triggers secretory lysosome exocytosis, resulting in the secretion of perforin and granzymes and target cell killing. Despite the pivotal role the secretory lysosome plays in NK cell function, how this organelle docks and fuses with the plasma membrane to facilitate the secretion of cytotoxic molecules is poorly understood. We are, therefore, using a combination of cell biological and proteomic techniques to identify the exocytic machinery and to dissect the role that these proteins play in NK cell cytotoxicity.

Many viruses infect and form life long infections in humans that have a fully functional immune system. We are investigating how viruses can escape detection by NK cells and cytotoxic T-lymphocytes.  Our most recent work focuses on BK virus, a human pathogen associated with graft failure in renal transplantation

 

 

 

 

Detailed research programme                  Close ▲
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Senior Lecturer in Cell Biology and Immunology (Leeds) 2002-
PhD (manchester)


PhD (Manchester) 1994
Postdoctoral fellow (Dundee) 1994-1996
Postdoctoral fellow (UCL) 1996-1998
Postdoctoral fellow (Cambridge) 1999-2002

9.58 Garstang South
School of Molecular and Cellular Biology
0113 343 3030
e.w.hewitt@leeds.ac.uk
http://www.fbs.leeds.ac.uk/staff/profile.php?tag=Hewitt_E

Selected Publications

  1. Tipping KW, van Oosten-Hawle P, Hewitt EW and Radford, SE. (2015). Amyloid Fibres: Inert End-Stage Aggregates or Key Players in Disease? Trends in Biochemical Sciences 40, 719-727

  2. Tipping KW, Karamanos TK, Jakhria T, Iadanza MG, Goodchild SC, Tuma R, Ranson NA, Hewitt EW, Radford SE. (2015). pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers. Proc Natl Acad Sci U S A 112: 5691-6

  3. Jakhria T, Hellewell AL, Porter MY, Jackson MP, Tipping KW, Xue WF, Radford SE, Hewitt EW. (2014) β2-microglobulin amyloid fibrils are nanoparticles that disrupt lysosomal membrane protein trafficking and inhibit protein degradation by lysosomes.  J Biol Chem. 289:35781-94.

  4. Hellewell AL, Foresti O, Gover N, Porter MY, Hewitt EW. (2014) Analysis of familial hemophagocytic lymphohistiocytosis type 4 (FHL-4) mutant proteins reveals that S-acylation is required for the function of syntaxin 11 in natural killer cells. PLoS One. 9:e98900.