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Search Results to Igor Kramnik, MD, PhD

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Research Expertise & Professional Interests 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.

One or more keywords matched the following items that are connected to Kramnik, Igor

Item TypeName
Concept Mycobacterium tuberculosis
Concept Tuberculosis
Concept Tuberculosis, Pulmonary
Concept Tuberculosis Vaccines
Academic Article T-helper 1-like subset selection in Mycobacterium bovis bacillus Calmette-Guérin-infected resistant and susceptible mice.
Academic Article [Cellular mechanisms of suppression of T-lymphocyte proliferation by lung cells in experimental tuberculosis].
Academic Article Distinct H-2 complex control of mortality, and immune responses to tuberculosis infection in virgin and BCG-vaccinated mice.
Academic Article I-A beta gene expression regulation in macrophages derived from mice susceptible or resistant to infection with M. bovis BCG.
Academic Article Identification of differentially expressed mRNA in prokaryotic organisms by customized amplification libraries (DECAL): the effect of isoniazid on gene expression in Mycobacterium tuberculosis.
Academic Article Susceptibility to tuberculosis as a complex genetic trait: analysis using recombinant congenic strains of mice.
Academic Article Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis.
Academic Article Ipr1 gene mediates innate immunity to tuberculosis.
Academic Article Increased susceptibility of mice lacking T-bet to infection with Mycobacterium tuberculosis correlates with increased IL-10 and decreased IFN-gamma production.
Academic Article Genetic architecture of tuberculosis resistance in a mouse model of infection.
Academic Article Regulation of T-cell proliferative responses by cells from solid lung tissue of M. tuberculosis-infected mice.
Academic Article Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa.
Academic Article Progression of pulmonary tuberculosis and efficiency of bacillus Calmette-Guérin vaccination are genetically controlled via a common sst1-mediated mechanism of innate immunity.
Academic Article Heme oxygenase-1-derived carbon monoxide induces the Mycobacterium tuberculosis dormancy regulon.
Academic Article Genetic dissection of host resistance to Mycobacterium tuberculosis: the sst1 locus and the Ipr1 gene.
Academic Article Multigenic control of tuberculosis resistance: analysis of a QTL on mouse chromosome 7 and its synergism with sst1.
Academic Article Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control.
Academic Article Man and mouse TB: contradictions and solutions.
Academic Article Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts.
Academic Article Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions.
Academic Article Evaluation of a mouse model of necrotic granuloma formation using C3HeB/FeJ mice for testing of drugs against Mycobacterium tuberculosis.
Academic Article Genetic dissection of pulmonary tuberculosis: implications for drug and vaccine development.
Academic Article [Suppression of immune response by lung cells in experimental tuberculosis].
Academic Article An unbiased genome-wide Mycobacterium tuberculosis gene expression approach to discover antigens targeted by human T cells expressed during pulmonary infection.
Academic Article Genetic control of host susceptibility to tuberculosis
Academic Article Nitrite production by macrophages derived from BCG-resistant and -susceptible congenic mouse strains in response to IFN-gamma and infection with BCG.
Academic Article Limited activity of clofazimine as a single drug in a mouse model of tuberculosis exhibiting caseous necrotic granulomas.
Academic Article SP110b Controls Host Immunity and Susceptibility to Tuberculosis.
Academic Article New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles.
Academic Article Lung necrosis and neutrophils reflect common pathways of susceptibility to Mycobacterium tuberculosis in genetically diverse, immune-competent mice.
Academic Article Mouse models of human TB pathology: roles in the analysis of necrosis and the development of host-directed therapies.
Academic Article Spatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma.
Academic Article Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra.
Academic Article The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection.
Academic Article Publisher Correction: Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra.
Grant Genetic-based susceptibility to pulmonary tuberculosis

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  • Tuberculosis