Host Defence Peptides:

Their Role in Immunity and Inflammatory Disease

 

Summary

Diseases of the airway are now killing more people in the U.K. than coronary heart disease. Airway disease is exacerbated by the rise of respiratory pathogens with a multi antibiotic resistant phenotype- so called “super bugs”. My research interests are centred around respiratory disease with particular emphasis on cystic fibrosis (CF). In CF individuals, chronic bacterial infection, inflammation and lung damage is the reason why this disease results in death in young adulthood. Super bugs complicate the phenotype and reduce life expectancy.

 

 

Derf1 monomer

 

Selected/Key Publications

1. Macpherson, H.; Keir, P.; Webb, S.; Samuel, K.; Boyle, S.; Bickmore, W.; Forrester, L. and Dorin, J. Bone marrow-derived SP cells can contribute to the respiratory tract of mice in vivo. J Cell Sci 118( 11):2441-2450, 2005
   PubMed Abstract
2. Campopiano, D.J.; Clarke, D.J.; Polfer, N.C.; Barran, P.E.; Langley, R.J.; Govan, J.R.; Maxwell, A. and Dorin, J.R. Structure-activity relationships in defensin dimers. A novel link between beta -defensin tertiary structure and antimicrobial activity. J Biol Chem 279(47):48671-48679, 2004
   PubMed Abstract
3. Morrison, G.M.; Semple, C.A.M.; Kilanowski, F.M.; Hill, R.E. and Dorin, J.R. Signal sequence conservation and mature peptide divergence with subgroups of the murine beta-defensin gene family. Molecular Biology of Evolution 20(3):460-470, 2003
   PubMed Abstract
4. Dickinson, P.; Smith, S.N.; Webb, S.; Kilanowski, F.M.; Campbell, I.J.; Taylor, M.S.; Porteous, D.J.; Willemsen, R.; de Jonge, H.R.; Farley, R.; Alton, E.W. and Dorin, J.R. The severe G480C cystic fibrosis mutation, when replicated in the mouse, demonstrates mistrafficking, normal survival and organ-specific bioelectrics. Hum Mol Genet 11(3):243-251, 2002
   PubMed Abstract
5. Morrison, G.; Kilanowski, F.; Davidson, D. and Dorin, J. Characterization of the mouse beta defensin 1, Defb1, mutant mouse model. Infect Immun 70(6):3053-3060, 2002
   PubMed Abstract
   

 

Lab Members

Current lab members involved in this work are:

• Fiona Kilanowski
• Christine Tyrrell
• Dr Heather MacPherson
• Sheila Webb
• Dr Fiona Semple

 

My main direction is to:

1. Investigate the in vivo function of the ß-defensin gene family of Host-Defence peptides and their potential as therapeutics. (this page)

 

 

ß-defensins-understanding the Body's Own Defence

One area of work is in a family of small peptides (ß-defensins) that are naturally occurring antibiotics produced primarily by cells exposed to the environment. These genes are part of the first defence individuals have against bacteria and viruses. This defence process is particularly important in the lung, which is continually assaulted by a variety of microbes. The ß-defensin gene family is present in birds and mammals and has become large due to expansion by gene duplication. We have isolated novel genes from both human and mouse and shown that different species have different repertoires of genes and these have evolved due to rapid positive Darwinian selection. That is, amino acid sequence changes that result in a new or improved function have been selected so that gene sequence changes more quickly than expected. This has indeed been a very rapid process and indicates the strong selective pressure exerted by needing to acquire resistance to pathogens.

 

Purpose

Our goals in studying these genes in both human and mouse are to clarify their function in vivo, understand their evolution, determine any important clues for the design of novel antibiotics and consider their potential as therapeutics.

 

Approach, Progress and Future Work

We have made KO mice of the mouse orthologue of the first ß-defensin discovered (DEFB1). This mouse had no overt phenotype1 and we then discovered that it was part of a multigene array that included 27genes2. We are currently deleting this locus using a lox-cre approach.

We have also identified several novel murine specific genes as well as those with clear human orthologues. We can show that the evolution of these genes is complex and they exhibit both positive and negative selection 3-5.

In collaboration with the School of Chemistry and Medical Microbiology at Edinburgh University and we are identifying residues important in the function of these genes and are extending the in vitro structure activity relationship (SAR) studies to in vivo6-9. Recent work has shown that the chemotactic properties of ß-defensins for CD4 T cells and immature dendritic cells through chemokine receptor 6, identify them as an important link between adaptive and innate immunity. We are currently trying to identify a novel receptor that these molecules must act through.