Project Leaders:
Robert W.E. Hancock, Lorne Babiuk

Involved Institutions:   
University of British Columbia, University of Saskatchewan

Technology Applications:   
Novel therapeutic approaches to infectious diseases

Research Funding Program:   
Competition III

GE³LS Activity:   
Moving Science Out of the Laboratory: Why are Some Scientists More Translational than Others?

Despite being exposed to tens of thousands of potentially pathogenic microbes daily, we rarely succumb to infection, primarily due to our innate immune system. Innate immunity, conserved between animals from insects to man, is a relatively non-specific system recognizing microbial signature molecules that is immediately available or rapidly activated. Unfortunately, if it is over-stimulated, there can be excessive inflammation, leading to tissue damage and deadly syndromes like sepsis. In a previous project, the researchers described genes up-regulated during the triggering of innate immunity as well as a novel therapeutic approach to infectious diseases that selectively boosts innate immunity while suppressing harmful inflammation. This project will characterize selected genes in response to Salmonella infection in mouse models. By deleting specific genes, their relevance in human and animal infections will be determined. An understanding of the innate immune system will allow investigators to further understand the points for intervention to resolve infection without causing excessive inflammation.

Pathogenomics describes genomic approaches to studying the interactions between pathogens and their hosts. An initial step in microbial pathogenesis is overcoming the host’s innate immunity because the interaction of microbes with host cells triggers this response to combat infection. Although increasing innate immunity should prevent more infections, too much immune response can lead to excessive inflammation and can have disastrous consequences such as tissue damage or sepsis. Therefore, this project aims to understand the upregulation of innate immunity to determine the points of intervention that will allow control of infection without harmful inflammation.

In a previous project, the Functional Pathogenomics of Mucosal Immunity Program, researchers used a comparative genomics approach to identify genes that were up-regulated at the initiation of innate immunity. For this project, mouse models will be used that are challenged by Salmonella infection. Not only is Salmonella a major cause of infection but this will continue the previous comparative genomics work.

Key genes involved in innate immunity will be deleted one at a time in mice and, where appropriate, combined in F1 crosses. Then the interaction between Salmonella and the knock-out mouse and its tissues and/or cells will be analyzed with microarrays, protein chips, and functional assays. Genes will also be deleted or over-expressed in cells from humans and cattle for comparative genomic extrapolation to other species. The researchers will also build a database, innateDB, of the genes and interactions involved in innate immunity.

This project involves major international partnerships with the world renowned Sanger Institute, the National University of Singapore, and a bioinformatics team at Trinity College Dublin.