Associate Professor, Medicine Director, Aerobiology Core
The emergence and global spread of infections caused by multidrug resistant and extensively drug resistant forms of Mycobacterium tuberculosis (M.tb) highlighted the importance of better understanding the tuberculosis pathogenesis in order to develop rational interventions to cure the disease and prevent epidemics.
For millennia, M.tb co-existed with humans causing more death than any other known infectious agent. The key element of the evolutionary successful virulence strategy of this intracellular pathogen is its ability to cause destruction in the lungs of susceptible individuals and to spread via aerosols, infecting the respiratory system of new hosts. The bacterial and hosts determinants of the lung tropism and destruction remain unknown.
We explore the pathogenesis of pulmonary tuberculosis using a mouse model for immunological and genetic analysis. As in humans, M.tb predominantly attacks mouse lungs causing various forms of the disease. In both species, the outcomes of the infection to a great extent are determined by the host genetic composition. Using forward genetic analysis we have identified and characterized major genetic loci synergistically controlling progression of pulmonary tuberculosis. A unique genetic locus sst1 (supersusceptibility to tuberculosis 1) controls the development of necrosis within tuberculosis granulomas in a lung-specific manner. Using positional cloning, we have identified a strong candidate gene within the sst1 locus, the Ipr1 (intracellular pathogen resistance 1) gene. Finding the mechanism, through which the Ipr1-encoded protein controls anti-tuberculosis immunity at biochemical, cellular, tissue-specific and whole organism levels, presents the next challenge.
We also pursue characterization of novel genetic loci on chromosomes 7, 15 and 17. Revealing polymorphic genes encoded within the new loci, their individual functions and interactions will allow untangling complex genetic control of host resistance and susceptibility to tuberculosis.
A set of congenic mouse strains generated in the above studies carry various combinations of the tuberculosis resistance alleles and display different forms of the pulmonary disease following M.tb. challenge. We are developing tools for live imaging and functional assessment of the granuloma forming cells during the course of infection in genetically resistant and susceptible hosts. Modeling host–pathogen interactions in diverse, but genetically defined, hosts is also important for the characterization of the pathogen’s virulence genes, as well as the mechanisms of its adaptation and evolution under pressures generated by host immunity and anti-tuberculosis therapy.
Focused on key pathogenically relevant phenotypes in vivo, forward genetic analysis often revealed previously unknown disease pathways and biological processes. We anticipate that our work will build experimental and theoretical foundations for understanding tuberculosis granuloma as a unique and dynamic tissue, in which various immunological and homeostatic processes interact to shape the trajectory of host–pathogen interactions. This knowledge will help explain failures of anti-tuberculosis vaccines and drugs, and provide new directions for preventing and curing pulmonary tuberculosis.
- Pichugin, A., B-S. Yan, L. Kobzik, and I. Kramnik. 2009. Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. Amer. J. Pathol. 174:2190-2201.
- Sissons, J., B-S. Yan, A. Pichugin, A. Kirby, M.J. Daly and I. Kramnik. 2009. Multigenic control of tuberculosis resistance: analysis of a QTL on mouse chromosome 7 and its synergism with sst1. Genes Immun. Jan;10(1):37-46.