Genetics of nematode development and innate immunity

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.

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.