Welcome to the CIHR Team in Mutagenesis and Infectious Diseases Homepage
Despite past progress in areas such as vaccination, hygiene and antimicrobials, the extent and impact of infectious diseases on both developed and developing nations is regaining added prominence in the 21st century, and this worrisome trend is now a leading issue on the global health agenda of policymakers and political leaders. Host response mechanisms against infections such as enterobacteria, malaria and influenza are only partially understood and it is unclear how these pathogenic organisms delay, block or escape the development of sterilizing immunity.
Mendelian genetic variants in humans and mice have provided key insights into mechanisms of host resistance to infection, as illustrated by the analysis of variants in genes encoding NRAMP1, TLR4, and NK cell receptors, to which members of this consortium have been significant contributors. By beginning with phenotypic variation, such genetic approach reveals entirely new genes and mechanisms, whether they be ion transport in phagosomes (Nramp), or connections between innate and adaptive immune responses (NK receptors, TLR4). Additionally, access to the current human and mouse genome sequence makes it possible to study variation in orthologous genes from both species. The objective of our team aims to build on this productive strategy, bringing together complementary expertise and infrastructure to form the CIHR ENU Team in Mutagenesis and Infectious Diseases.
Our general goal is to create a unique, integrated, high throughput discovery platform that will accelerate the identification of novel host susceptibility genes against infection and establish their role in the intricate cellular and molecular cascades that mediate protective inflammation and robust immunity. This knowledge will enhance our fundamental understanding of human infectious disease pathogenesis and will be a strong basis for the development of diagnostic tools and innovative therapeutic strategies. Our specific aims will be:
Aim 1: Produce mouse libraries carrying homozygous single nucleotide substitutions induced by ENU chemical mutagenesis. ENU is a powerful mutagen which induces point mutations in the mouse genome. The identification of novel phenotypes of host susceptibility to infection induced by ENU has been validated by us and others.
Aim 2: Isolate new Mendelian mouse variants with altered resistance to infection in primary and secondary screens. The team will discover and map informative heritable variants in mice by infection in vivo with Salmonella Typhimurium, Plasmodium chabaudii, and influenza virus, and ex vivo for assessment of innate immunity via TLR and NLR pathways.
Aim 3: Identify and characterize mutations responsible for altered resistance to infection. The Team will pursue the identification of variants most likely to define new biochemical pathways and cellular mechanisms regulating host resistance to infection using positional cloning. In synergy with collaborators, the Team will seek to validate gene identification and protein function. New mutant mice will be distributed to key collaborators at the Centre for the Study of Host Resistance to perform comprehensive tertiary phenotyping for susceptibility to infection, biomarker analysis and response to vaccination.
AIM 4: Study the role of identified mutations in human patients. The Team will clone and sequence human orthologous genes to initiate the study of samples from immunodeficient patients of presumed Mendelian inheritance or affected populations, and will liaise with clinical collaborators.
A Bioinformatics core will provide lateral support by ensuring efficient, reliable, backed-up storage of the data produced at the various stages of the program. In addition, the Bioinformatics core will support data mining for paralogous genes and prediction of function.Priorities in the pursue of novel phenodeviants, gene identification and human studies will be established in concert with a Scientific Advisory Board consisting of world leaders in ENU mutagenesis, mouse and human experts in infectious diseases.
Overall, our team approach provides clear synergy and a cross-cutting capacity to our research design, afforded by the implementation of cell biology, biochemistry and genetic platforms to study host-pathogen interactions in the context of the genetic determinants generated by ENU mutagenesis. Such an ambitious endeavor is only possible by virtue of Team work.