Igor Kramnik, M.D., Ph.D.
Associate Professor of Medicine
Control of tuberculosis (TB) remains a global health priority despite a significant decrease in its prevalence within the past century. New challenges have emerged with the appearance of drug resistant forms of M.tb and the realization that the existing BCG vaccine is not sufficiently effective to eradicate the disease. Thus, the emergence and spread of drug resistant forms of Mycobacterium tuberculosis (M.tb) represents a significant global threat of re-emerging epidemics of TB with no effective therapies in sight.. Given the dearth of new drugs targeting the pathogen, interventions targeting host cells are urgently needed. However, our limited understanding of the virulence stragegy of M.tb remains a major obstacle to its complete eradication. In our view two major gaps exist on the host side: what makes some immunocompetent individuals more susceptible to M.tb than the majority of the population, and what makes the lungs an organ that is particularly vulnerable to M.tb. The lung is central to the virulence strategy of M.tb, because aerosol is the only epidemiologically significant route of M.tb transmission in human populations. Interventions that target the lung to enhance mechanisms of local immunity and prevent lung damage may produce the biggest epidemiological impact by preventing M.tb transmission.
We pursue identification of pathways exploited by the pathogen in the lungs of susceptible individuals – a critical node in the extremely successful evolutionary strategy of M.tb - and the development of targeted interventions. Our lab and collaborators described a novel mouse model of human-like pulmonary tuberculosis. The key element of this model is the development of well organized necrotic granulomas, which closely resemble the human disease, specifically in the lungs of otherwise immunocompetent mice. Using forward genetic analysis we identifed the sst1 locus as the one responsible for necrotization of the lung granulomas and identified the candidate gene Ipr1 using positional cloning. We have found that the Ipr1 protein is an interferon-inducible chromatin-associated protein involved in control of macrophage activation and death. Our current efforts are focused on understanding the Ipr1-mediated biochemical pathways and their role in host resistance to infections, control of lung inflammation and tissue damage. In addition we have developed a screening strategy to identify compounds that enhance the Ipr1 function, which can be developed into novel drugs that increase host resistance to M.tuberculosis and related infections.
During the course of these studies we documented the development of lung squamous cell carcinomas (SSC) at the chronic stages of tuberculosis infection. Because squamous cell carcinomas do not occur in our mouse strains spontaneously, we concluded that M.tb infection was sufficient for both initiation and progression of lung SCC. These findings experimentally proved a causal link between tuberculosis and lung cancers, recently confirmed by epidemiological analysis in humans. Thus the TB-infected lung presents a destabilizing environment for epithelial cells, yet factors influencing epithelial cell function in the context of chronic infection have not been much studied. We study lung epithelial cells over the course of TB infection to understand mechanisms of their injury, repair, and neoplastic transformation in order to develop interventions that restore epithelial cell homeostasis and prevent initiation of lung tumors during TB progression.
- Kramnik, I. 2008 Genetic Dissection of Host Resistance to Mycobacterium tuberculosis: the sst1 locus and the Ipr gene. In: Current Topics in Microbiology and Immunology, Immunology, Phenotype First: How Mutations Have Established New Principles and Pathways in Immunology, Beutler, Bruce (Ed.), Vol. 321:123- 148.
- 8. Sissons, J., Yan, B.-S., Pichugin, A., Kirby, A., Daly, M.J., and Igor 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. PMCID: PMC167821
- Alexander Pichugin, Bo-Shiun Yan, Lester Kobzik and Igor Kramnik. 2009. Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. American Journal of Pathology 174, 2190-2201. PMCID: PMC2684184
- 10. Angele Nalbandian, Bo-Shiun Yan, Alexander Pichugin, Roderick Bronson and Igor Kramnik. 2009. Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control. Oncogene, 28, 1928-1938. PMCID: PMC Journal – In Process
- 11. Alexander Apt and Igor Kramnik. Man and mouse TB: contradictions and solutions. 2009. Tuberculosis (Edinb) 89, 195-198. PMCID: PMC2705810
- 12. Harper, J., C. Skerry, S. L. Davis, R. Tasneen, M. Weir, I. Kramnik, W. R. Bishai, M. G. Pomper, E. L. Nuermberger, and S. K. Jain. 2012. Mouse Model of Necrotic Tuberculosis Granulomas Develops Hypoxic Lesions. J Infect Dis. Epub. Dec 23, 2011.
- 13. Yang, C. S., J. S. Lee, M. Rodgers, C. K. Min, J. Y. Lee, H. J. Kim, K. H. Lee, C. J. Kim, B. Oh, E. Zandi, Z. Yue, I. Kramnik, C. Liang, and J. U. Jung. 2012. Autophagy protein Rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation. Cell Host Microbe 11:264-76.