Host Defense against Fungal Pathogens
The rapid pace of societal and technological change in the past several decades coupled with increases in susceptible human populations through aging, greater chronic disease burden, and immune suppression has facilitated the emergence and reemergence of a wide spectrum of infectious diseases. Several fungal pathogens have been specifically identified as a growing microbial threat to human health, yet compared to bacteria and viruses, very little is known about mammalian host resistance to fungal infection and current therapeutic options are quite limited. To advance the understanding of human fungal diseases and develop a rational framework for the creation of improved treatments, we are characterizing the molecular basis of robust immunity against several endemic and opportunistic mycoses using mouse models to genetically dissect the individual loci responsible for differential host resistance.
Activation Pathways of the Innate Immune System
Prompt recognition of infection is mediated by pattern recognition receptors (PRRs) of the innate immune system that detect conserved structures unique to microbes. This leads to rapid activation of inflammatory responses that contain the infection and instruct the adaptive immune system to generate a specific, long-lasting, and definitive response. Several classes of PRRs have been identified (such as the Toll-like receptors) although others exist and the associated signaling pathways for most PRRs are not well defined. We are using phenotypic screening and genetic analysis of conventional and novel mouse strains to identify novel PRRs and elucidate the pathways activated downstream of microbial recognition. This information will significantly enhance our understanding of the molecular basis of the innate immune response to microbial infection.
Novel Host Resistance Susceptibility Genes
The function of the majority of predicted proteins encoded by the human genome sequence is unknown. Ninety-nine percent of these genes have a counterpart in the laboratory mouse, signifying a conserved biological role. Induction of novel variation through random chemical mutagenesis with N-ethyl N-nitrosourea (ENU) is an exciting forward (phenotype-driven) genetic approach to unravel the complexities of gene function and has been successfully applied in fruit flies and nematode worms. To extend these studies to host defense of infectious diseases in mammalian systems, I am a member of a McGill team led by Dr. Silvia Vidal that has established a platform for high throughput screening of ENU-mutagenized mice in order to identify defective host resistance against all major classes of human microbial pathogens. The specific genetic alterations underlying these newly identified mutants will be used to create an enhanced map of the molecular circuitry underlying the immune response to infection.
RI-MUHC, Block E
1001 Decarie Blvd.
Montreal QC H4A 3J1
Tel: 514-934-1934 Ext. 44654 (lab)
Tel: 514-934-1934 Ext. 44626 (office)
Tel: 514-934-1934 Ext. 76172 (admin)
Education & Training
MD, U Alberta, 1987
Int Med, Mayo Clin, 1988-91
Inf Dis, U Manitoba, 1991-1994
Pulm CC Med, Yale. 1999-2001
McGill Cntr Host Res, 1994-1999