Genetics of nematode development and innate immunity

Lead Research Organisation: University of Oxford
Department Name: Biochemistry

Abstract

Better understanding of developmental processes, responses to infectious stress and mechanisms of defense against bacterial infection are all central to medical progress. This project aims to investigate these processes in a simple and very tractable system, the tiny nematode worm C. elegans, which can be infected by a nematode-specific bacterium called M. nematophilum. We are interested in studying medically relevant questions in this system, such as how pathogenic bacteria are able to infect their hosts, how the host is able to detect bacteria and activate defensive reactions, and what kinds of molecules are used to combat infection. Nematodes cannot make antibodies, so they may use different kinds of immunity from mammals. The M. nematophilum bacterium also causes shape change in infected worms, allowing investigation of several questions in developmental biology. Lastly, the infection provides a new way to study the surface of nematodes, which is relevant to the control of parasitic nematodes, many of which are medically or economically important.

Technical Summary

The interaction between the nematode Caenorhabditis elegans and the nematode pathogen Microbacterium nematophilum involves bacterial attachment followed by morphological change in the infected worm, seen as conspicuous tail swelling. The shape change has been shown to be a defensive reaction caused by ERK MAP kinase activation in rectal epithelial cells, and is associated with induction of putative defense proteins. Numerous C. elegans mutants affecting either bacterial attachment or the swelling response have been characterized genetically and molecularly. Many of the mutants defective in bacterial attachment also affect cuticle integrity and other surface properties. At least one of the genes concerned is essential for embryogenesis, and several are required for forming normal permeability barriers.
The worm/pathogen interaction has provided a novel and powerful way to address a number of questions in development and cell biology, as well as providing a new paradigm for studying innate immunity. Further research is planned along the following interconnected lines:
A. Analysis of signal transduction processes leading to cell swelling and defense.
B. Investigation of the mechanism of specific cell swelling.
C. Analysis of genes affecting epithelial integrity.
D. Analysis of genes affecting cuticle surface properties.
E. Analysis of cuticle collagen processing, assembly and effects on morphology.
F. Investigation of C-type lectins and lysozymes as innate immunity effectors.

Publications

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publication icon
Gravato-Nobre MJ (2008) The acyltransferase gene bus-1 exhibits conserved and specific expression in nematode rectal cells and reveals pathogen-induced cell swelling. in Developmental dynamics : an official publication of the American Association of Anatomists

 
Description MRC Programme Grant
Amount £1,688,936 (GBP)
Funding ID G0600238 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2006 
End 03/2012
 
Title Drug-sensitive nematode strains 
Description We have developed a series of mutant strains of the nematode C. elegans with greatly increased sensitivity to many different drugs, arising from altered cuticle permeability. 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact General improvement in the ability to use C. elegans for drug screening and pharmacological manipulation. 
 
Title Nematode bacterial pathogens 
Description Strains of novel bacterial pathogens of nematodes 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact None as yet 
 
Description Nematode glycobiology 
Organisation Food and Drug Administration (FDA)
Department Centre for Biologics Evaluation and Research
Country United States 
Sector Public 
PI Contribution Provision of mutant and transgenic nematode lines, phenotypic investigation by microscopy and cell biology
Collaborator Contribution Mass-spec analysis of nematode glycans
Impact PMID: 20385555
Start Year 2008
 
Description Yersinia biofilm formation 
Organisation University of California, San Francisco
Department Department of Cell and Tissue Biology
Country United States 
Sector Academic/University 
PI Contribution Molecular cloning, expression analysis and phenotypic characterization of genes affecting nematode surface properties
Collaborator Contribution Testing of pathogenicity and biofilm formation by Yersinia bacteria
Impact PMID: 20980242
 
Description meiosis research 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution Genetic and phenotypic data, mutant isolation
Collaborator Contribution Molecular and cytological data
Impact PMID: 17237503
 
Description nematode galactofuranose 
Organisation New England Biolabs
Country United States 
Sector Private 
PI Contribution Genetic, phenotypic and pathogenesis susceptibility data
Collaborator Contribution Molecular, genetic and cytological data
Impact PMID: 19751718
Start Year 2006
 
Description nematode transcription termination 
Organisation University of Oxford
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Genetic and transgenic strain construction, phenotype analysis, microscopy
Collaborator Contribution Molecular data and methods
Impact .PMID: 19740764
Start Year 2006
 
Description Art and Science in Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I organized a public meeting in Jan 2006, on Art and Science in Oxford, in relation to the Salt Bridges Arts Programme for the New Biochemistry building. This included description of my research.

Increased awareness of biochemical and medical research, and its relationship to the arts. Increased funding for art/science projects.
Year(s) Of Engagement Activity 2006
 
Description Salt Bridges Science/Art Programme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I organized public meetings, exhibitions, science outreach training sessions associated with the Salt Bridges arts programme for the New Biochemistry building in Oxford, and the biomedical research therein. I have had multiple interviews with architectural and scientific journalists in UK and Europe, resulting in articles in the general media.

Increased science/art interactions; greater public profile for biochemical and medical research.
Year(s) Of Engagement Activity 2007,2008,2009