Grant: Foundation Grant

<html> <body> <p> <strong>Field of Study:</strong> Tuberculosis (TB) and leprosy, caused by <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) and <em>Mycobacterium leprae</em>, respectively, are the two most common human mycobacterial diseases. Present control of both diseases is severely impeded by lack of broadly effective treatments, vaccines and diagnostic tests for disease progression. We propose to employ methods of genetic epidemiology, human genetics and systems biology to foster development of rapid and specific diagnostic tests, next generation drugs and efficacious vaccines.<br> <br> We aim to identify the host genetic factors that associate with susceptibility to infection, disease development and severe adverse effects in both diseases. To validate the functional consequences of these associations, typically observed in non-coding regions, we will establish their impact on the transcriptome response of host dendritic cells and macrophages, the key cells where mycobacteria gain entry and replicate. Expression programs will be profiled for different patient subtypes and genetic susceptibility factors will be integrated into the host response networks. In addition, we will study the impact of epigenetic modifications on clinical disease. Finally, gene expression signatures for infection and progression to disease will be obtained and genetic modifiers of the host response will be determined employing expression quantitative trait locus (eQTL) analysis in samples from two prospective cohorts.<br> <br> <strong>Outcome Impact:</strong> An anticipated result of our experiments is the definition and functional validation of the main genetic vulnerabilities that govern the host-pathogen interplay in TB and leprosy. By combining genetic susceptibility with systems biology we will identify specific immune mechanisms that are protective for infection and/or disease and thus leverage both innovative host tailored therapies and vaccine development. In addition, we expect to identify transcriptome signatures for infection and for progression from infection to disease for leprosy. Similar signatures are available for TB and we will define the underlying eQTLs for all signatures. Our results will lead to either gene expression or SNP based diagnostics for latent infection and risk of progression from infection to disease, two key problems for eradication of leprosy and control of TB. Hence, the expected results will provide critical knowledge of disease pathogenesis with high impact on disease control.<br> <br> <strong>Expertise:</strong> Our expertise is host genetics of TB and leprosy and we have assembled a group of experts who are global leaders in this field. We have a long history of successful investigations with most of these experts, including those in endemic countries. The thorough understanding of the diverse clinical manifestations, superior knowledge of the epidemiological situation at each site, advanced genetic analysis methodology, and the use of cutting edge genomics technology make our group unique in Canada and an international leader.<br> <br> <strong>Mentorship:</strong> Since our group is engaged heavily in international research, capacity building and research training of students, clinicians and researchers from collaborating groups is an important part of our mentorship activities. The emphasis of graduate student training is on a solid foundation in genetic epidemiology, which by definition is multi-disciplinary, while for postdoctoral trainees we emphasize more translational aspects of our studies, especially those with a potential commercial interest.</p> </body> </html>