June 2014 Lab of the month - Neil Mabbott

Neil Mabbott’s lab is based at the Roslin Institute at Easter Bush.

The lab is currently home to a great team of postdocs - David Donaldson and Vivian Turner -  and PhD students - Barry Bradford, Claire Davies, Mari Pattison and Anuj Sehgal.

L to R:  Neil Mabbott, Vivian Turner, Mari Pattison, Anuj Sehgal and the Roslin Institute

Before arriving at the Roslin Institute, Neil completed his Ph.D. in Jerry Sternberg’s lab at the University of Aberdeen in 1995 where he studied the role of nitric oxide as an immunosuppressive mediator during African trypanosomiasis infections.  He then moved to the Institute for Animal Health where he began to study the pathogenesis of prion diseases, specifically how they appear to “hi-jack” the immune system to spread from the site of exposure, to the brain where they cause neurodegeneration.  After many years devoted almost entirely to the study of prion pathogenesis, recent activities in the group are allowing Neil to go back to his parasitology routes by studying the effects of co-infection with helminths on prion diseases.

There are three major lines of research currently in the lab

The main focus of research in Neil’s lab is to understand the pathogenesis of infectious diseases within the immune system.  In particular he and his colleagues are interested in understanding host-pathogen interactions within the mucosal immune system, especially prion diseases and also in other gastrointestinal pathogens such as Salmonella and nematodes.  More widely Neil’s work is helping to understand how inflammation and aging affect the immune system and influence susceptibility to infectious diseases.  A systems biology approach is also being developed and is being used to compare the transcriptomic profiles of distinct immune cell populations and identify new cell-specific genes.

How prions get from the gut to the brain

Many prion diseases, including variant Creutzfeldt-Jakob disease in humans (CJD), bovine spongiform encephalopathy, chronic wasting disease in mule deer and elk, and sheep scrapie are acquired by eating prion-contaminated food.  Work in Neil's lab and others, has show that after oral exposure, prions often accumulate first in gut associated lymphoid tissues (for example in the intestinal Peyer’s patches) as they make their journey from the gut to the brain.  They have also shown that in mice lacking the epithelial cells overlying the Peyer’s patches (M cells), oral exposure to prions does not lead to development of clinical diseases indicating that the accumulation of prions in Peyer's patches is a obligate requirement for their efficient delivery to the brain. 

PhD student Anuj Seghal and postdoc David Donaldson in the lab are continuing this work, and PhD student Barry Bradford is also determining whether migratory dendritic cells deliver prions to Peyer’s patches once they have cross the gut epithelium.  Work is also underway to investigate the effects on prion uptake of co-infections with gut parasites such as the nematode Trichuris muris.

Listen to Neil talking about his work on gut associated lympoid tissue and their effect on oral prion susceptibility at the Edinburgh Infectious Diseases symposium in May 2014.  (Link to video on YouTube)

Why younger people are more susceptible to prion disease

The average age of patients with variant CJD is 28 but it has been unclear as to why older people are not as affected by the disease.  This is another topic currently being addressed by the Mabbott lab.  It is well know that as we age the function of our immune system declines, which amongst other things, is associated with lower levels of protective immunity and an increase in inflammation and autoimmunity. In previous work the Mabbott lab showed that early replication of prions upon follicular dendritic cells in the secondary lymphoid organs was crucial for the spread of disease to the brain.  The function of these cells is dramatically impaired in the lymphoid tissues of aged mice.  Their recent work has shown that the FDC in aged mice are unable to trap and replicate prions, and as a consequence, do not develop clinical disease after peripheral exposure.   His studies suggest that the effects of aging on the immune system may impede the spread of prions to the brain and may help explain why most cases of variant CJD to-date have predominantly occurred in younger people.

PhD student in the lab Mari Pattison, is now using multiphoton microscopy to compare the dynamic interactions between the immune systems and antigens in young and old mice to understand these results in more detailNew postdoc Vivian Turner is determining how aging adversely affects the microarchiture in the spleen and the consequences this has on host immunity.

Some of the beautiful confocal microscopy images generated by Neil and his team in their research:  (L) Whole mount intestinal Peyer's patch, the critical gateway for TSE infection; (M) Intestinal Peyer's patch with the cells through which prion proteins traverse stained in green; (R) Fluorescent macrophages (green) resident in an intestinal Peyer's patch

Comparing the transcriptomic profiles of distinct immune cell populations

Most major journals and funders now require that micro array expression data sets are deposited in public depositories such as NCBI Gene Expression Omnibus and ArrayExpress. The public availability of these data permits meta-analysis of data produced in different laboratories. The challenge then is to generate useful information from this microarray data deluge.  Neil has employed the network tool BioLayout Express3D which was specifically developed by colleagues at the Roslin Institute (Prof. Tom Freeman) to allow the visualisation of coexpression relationships in large datasets.  This approach as been used to compare the transcriptomes of different macrophage and B-cell subsets, and to identify novel genes in the gut epithelium. 

Key publications from the lab

  • Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy Brown KL and Mabbott NA 2014 J Gen Virol  Vol:95 Pages: 231-243 http://www.ncbi.nlm.nih.gov/pubmed/24123519
  • Aging and the mucosal immune system in the intestine NA Mabbott, A Kobayashi, A Sehgal, BM Bradford, M Pattison, DS Donaldson.  Biogerontology http://www.ncbi.nlm.nih.gov/pubmed/24705962
  • The functional maturation of M cells is dramatically reduced in the Peyer's patches of aged mice A Kobayashi, D S Donaldson, C Erridge, T Kanaya, I R Williams, H Ohno, A Mahajan, N A Mabbott.  Mucosal Immunol 2013, Vol: 6 Pages: 1027-1037 http://www.ncbi.nlm.nih.gov/pubmed/23360902
  • B Cell-Specific S1PR1 Deficiency Blocks Prion Dissemination between Secondary Lymphoid Organs S. W. Mok, R. L. Proia, V. Brinkmann, N. A. Mabbott.  Journal of Immunology 2012, Vol: 188 Pages: 5032-5040 http://www.ncbi.nlm.nih.gov/pubmed/22504650
  • M cell-depletion blocks oral prion disease pathogenesis D.S. Donaldson, A. Kobayashi, H. Ohno, H. Yagita, I.R. Williams, N.A. Mabbott.  Mucosal Immunology 2012,  Vol: 5 Pages: 216-225 http://www.ncbi.nlm.nih.gov/pubmed/22294048
  • Salmonella transforms follicle-associated epithelial cells into M cells to promote intestinal invasion. Tahoun A, Mahajan S, Paxton E, Malterer G, Donaldson DS, Wang D, Tan A, Gillespie TL, O'Shea M, Roe AJ, Shaw DJ, Gally DL, Lengeling A, Mabbott NA, Haas J, Mahajan A. Cell Host Microbe. 2012, 12(5):645-56 http://www.ncbi.nlm.nih.gov/pubmed/23159054
  • Prion uptake in the gut: identification of the first uptake and replication sites P. Kujala, C.R. Raymond, M. Romeijn, S.F. Godsave, S.I. van Kasteren, H. Wille, S.B. Prusiner, N.A. Mabbott, P.J. Peters.  PLoS Pathogens 2011, Vol: 7 http://www.ncbi.nlm.nih.gov/pubmed/22216002
  • Follicular Dendritic Cell-Specific Prion Protein (PrP) Expression Alone Is Sufficient to Sustain Prion Infection in the Spleen L. McCulloch, K.L. Brown, B.M. Bradford, J. Hopkins, M. Bailey, K. Rajewsky, J.C. Manson, N.A. Mabbott — Dec 2011 — PLoS Pathogens2011,  Vol: 7 http://www.ncbi.nlm.nih.gov/pubmed/22144895
  • The Effects of Host Age on the Transport of Complement-Bound Complexes to the Spleen and the Pathogenesis of Intravenous Scrapie Infection K.L. Brown, A. Gossner, S. Mok, N.A. Mabbott.  Journal of Virology, 2012, Vol: 86 Pages: 25-35 http://www.ncbi.nlm.nih.gov/pubmed

Read more about Neil's work

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