Keywords
Last Name

Igor Kramnik, MD, PhD

TitleAssociate Professor
InstitutionBoston University School of Medicine
DepartmentMedicine
DivisionPulmonary, Allergy, Sleep & Critical Care Medicine
Address620 Albany St
Boston MA 02118
Phone(617) 414-0344
ORCID ORCID Icon0000-0001-6511-9246
Other Positions
TitleAssociate Professor
InstitutionBoston University School of Medicine
DepartmentMicrobiology

TitleCenter Faculty Member
InstitutionBoston University School of Medicine
DepartmentPulmonary Center

TitleGraduate Faculty (Primary Mentor of Grad Students)
InstitutionBoston University School of Medicine, Division of Graduate Medical Sciences

InstitutionBoston Medical Center

 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.

 Publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Coppola M, van Meijgaarden KE, Franken KL, Commandeur S, Dolganov G, Kramnik I, Schoolnik GK, Comas I, Lund O, Prins C, van den Eeden SJ, Korsvold GE, Oftung F, Geluk A, Ottenhoff TH. New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles. Sci Rep. 2016 Nov 28; 6:37793. PMID: 27892960.
    View in: PubMed
  2. Leu JS, Chen ML, Chang SY, Yu SL, Lin CW, Wang H, Chen WC, Chang CH, Wang JY, Lee LN, Yu CJ, Kramnik I, Yan BS. SP110b Controls Host Immunity and Susceptibility to Tuberculosis. Am J Respir Crit Care Med. 2016 Nov 18. PMID: 27858493.
    View in: PubMed
  3. Bhattacharya B, Chatterjee S, Devine WG, Kobzik L, Beeler AB, Porco JA, Kramnik I. Fine-tuning of macrophage activation using synthetic rocaglate derivatives. Sci Rep. 2016 Apr 18; 6:24409. PMID: 27086720.
    View in: PubMed
  4. Kramnik I, Beamer G. Mouse models of human TB pathology: roles in the analysis of necrosis and the development of host-directed therapies. Semin Immunopathol. 2016 Mar; 38(2):221-37. PMID: 26542392.
    View in: PubMed
  5. Niazi MK, Dhulekar N, Schmidt D, Major S, Cooper R, Abeijon C, Gatti DM, Kramnik I, Yener B, Gurcan M, Beamer G. Lung necrosis and neutrophils reflect common pathways of susceptibility to Mycobacterium tuberculosis in genetically diverse, immune-competent mice. Dis Model Mech. 2015 Sep; 8(9):1141-53. PMID: 26204894.
    View in: PubMed
  6. Irwin SM, Gruppo V, Brooks E, Gilliland J, Scherman M, Reichlen MJ, Leistikow R, Kramnik I, Nuermberger EL, Voskuil MI, Lenaerts AJ. Limited activity of clofazimine as a single drug in a mouse model of tuberculosis exhibiting caseous necrotic granulomas. Antimicrob Agents Chemother. 2014 Jul; 58(7):4026-34. PMID: 24798275.
    View in: PubMed
  7. He X, Berland R, Mekasha S, Christensen TG, Alroy J, Kramnik I, Ingalls RR. The sst1 resistance locus regulates evasion of type I interferon signaling by Chlamydia pneumoniae as a disease tolerance mechanism. PLoS Pathog. 2013; 9(8):e1003569. PMID: 24009502.
    View in: PubMed
  8. Commandeur S, van Meijgaarden KE, Prins C, Pichugin AV, Dijkman K, van den Eeden SJ, Friggen AH, Franken KL, Dolganov G, Kramnik I, Schoolnik GK, Oftung F, Korsvold GE, Geluk A, Ottenhoff TH. An unbiased genome-wide Mycobacterium tuberculosis gene expression approach to discover antigens targeted by human T cells expressed during pulmonary infection. J Immunol. 2013 Feb 15; 190(4):1659-71. PMID: 23319735.
    View in: PubMed
  9. Lee MN, Roy M, Ong SE, Mertins P, Villani AC, Li W, Dotiwala F, Sen J, Doench JG, Orzalli MH, Kramnik I, Knipe DM, Lieberman J, Carr SA, Hacohen N. Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach. Nat Immunol. 2013 Feb; 14(2):179-85. PMID: 23263557.
    View in: PubMed
  10. Driver ER, Ryan GJ, Hoff DR, Irwin SM, Basaraba RJ, Kramnik I, Lenaerts AJ. Evaluation of a mouse model of necrotic granuloma formation using C3HeB/FeJ mice for testing of drugs against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012 Jun; 56(6):3181-95. PMID: 22470120.
    View in: PubMed
  11. Kramnik I. Genetic dissection of pulmonary tuberculosis: implications for drug and vaccine development. Nihon Hansenbyo Gakkai Zasshi. 2012 Apr; 81(1-2):13. PMID: 22586941.
    View in: PubMed
  12. Yang CS, Lee JS, Rodgers M, Min CK, Lee JY, Kim HJ, Lee KH, Kim CJ, Oh B, Zandi E, Yue Z, Kramnik I, Liang C, Jung JU. Autophagy protein Rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation. Cell Host Microbe. 2012 Mar 15; 11(3):264-76. PMID: 22423966.
    View in: PubMed
  13. Yang CS, Rodgers M, Min CK, Lee JS, Kingeter L, Lee JY, Jong A, Kramnik I, Lin X, Jung JU. The autophagy regulator Rubicon is a feedback inhibitor of CARD9-mediated host innate immunity. Cell Host Microbe. 2012 Mar 15; 11(3):277-89. PMID: 22423967.
    View in: PubMed
  14. Zhou H, DeLoid G, Browning E, Gregory DJ, Tan F, Bedugnis AS, Imrich A, Koziel H, Kramnik I, Lu Q, Kobzik L. Genome-wide RNAi screen in IFN-?-treated human macrophages identifies genes mediating resistance to the intracellular pathogen Francisella tularensis. PLoS One. 2012; 7(2):e31752. PMID: 22359626.
    View in: PubMed
  15. Harper J, Skerry C, Davis SL, Tasneen R, Weir M, Kramnik I, Bishai WR, Pomper MG, Nuermberger EL, Jain SK. Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions. J Infect Dis. 2012 Feb 15; 205(4):595-602. PMID: 22198962.
    View in: PubMed
  16. Cai L, Pan H, Trzcinski K, Thompson CM, Wu Q, Kramnik I. MYBBP1A: a new Ipr1's binding protein in mice. Mol Biol Rep. 2010 Dec; 37(8):3863-8. PMID: 20221700.
    View in: PubMed
  17. Aryee MJ, Gutiérrez-Pabello JA, Kramnik I, Maiti T, Quackenbush J. An improved empirical bayes approach to estimating differential gene expression in microarray time-course data: BETR (Bayesian Estimation of Temporal Regulation). BMC Bioinformatics. 2009; 10:409. PMID: 20003283.
    View in: PubMed
  18. Pichugin AV, Yan BS, Sloutsky A, Kobzik L, Kramnik I. Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. Am J Pathol. 2009 Jun; 174(6):2190-201. PMID: 19443700.
    View in: PubMed
  19. Apt A, Kramnik I. Man and mouse TB: contradictions and solutions. Tuberculosis (Edinb). 2009 May; 89(3):195-8. PMID: 19345146.
    View in: PubMed
  20. Nalbandian A, Yan BS, Pichugin A, Bronson RT, Kramnik I. Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control. Oncogene. 2009 Apr 30; 28(17):1928-38. PMID: 19330024.
    View in: PubMed
  21. Sissons J, Yan BS, Pichugin AV, Kirby A, Daly MJ, Kramnik I. Multigenic control of tuberculosis resistance: analysis of a QTL on mouse chromosome 7 and its synergism with sst1. Genes Immun. 2009 Jan; 10(1):37-46. PMID: 18784733.
    View in: PubMed
  22. Kumar A, Deshane JS, Crossman DK, Bolisetty S, Yan BS, Kramnik I, Agarwal A, Steyn AJ. Heme oxygenase-1-derived carbon monoxide induces the Mycobacterium tuberculosis dormancy regulon. J Biol Chem. 2008 Jun 27; 283(26):18032-9. PMID: 18400743.
    View in: PubMed
  23. Kramnik I. Genetic dissection of host resistance to Mycobacterium tuberculosis: the sst1 locus and the Ipr1 gene. Curr Top Microbiol Immunol. 2008; 321:123-48. PMID: 18727490.
    View in: PubMed
  24. Schurr E, Kramnik I. Genetic control of host susceptibility to tuberculosis. In: Handbook of Tuberculosis: Immunology and Cell Biology. Kaufmann SHE, Britton WJ (Eds.). WILEY-VCH Verlag. Weinheim, Germany. 2008; 295-336.
  25. Yan BS, Pichugin AV, Jobe O, Helming L, Eruslanov EB, Gutiérrez-Pabello JA, Rojas M, Shebzukhov YV, Kobzik L, Kramnik I. Progression of pulmonary tuberculosis and efficiency of bacillus Calmette-Guérin vaccination are genetically controlled via a common sst1-mediated mechanism of innate immunity. J Immunol. 2007 Nov 15; 179(10):6919-32. PMID: 17982083.
    View in: PubMed
  26. Pan H, Mostoslavsky G, Eruslanov E, Kotton DN, Kramnik I. Dual-promoter lentiviral system allows inducible expression of noxious proteins in macrophages. J Immunol Methods. 2008 Jan 1; 329(1-2):31-44. PMID: 17967462.
    View in: PubMed
  27. Tosh K, Campbell SJ, Fielding K, Sillah J, Bah B, Gustafson P, Manneh K, Lisse I, Sirugo G, Bennett S, Aaby P, McAdam KP, Bah-Sow O, Lienhardt C, Kramnik I, Hill AV. Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa. Proc Natl Acad Sci U S A. 2006 Jul 5; 103(27):10364-8. PMID: 16803959.
    View in: PubMed
  28. Yan BS, Kirby A, Shebzukhov YV, Daly MJ, Kramnik I. Genetic architecture of tuberculosis resistance in a mouse model of infection. Genes Immun. 2006 Apr; 7(3):201-10. PMID: 16452998.
    View in: PubMed
  29. Sullivan BM, Jobe O, Lazarevic V, Vasquez K, Bronson R, Glimcher LH, Kramnik I. Increased susceptibility of mice lacking T-bet to infection with Mycobacterium tuberculosis correlates with increased IL-10 and decreased IFN-gamma production. J Immunol. 2005 Oct 1; 175(7):4593-602. PMID: 16177104.
    View in: PubMed
  30. Pan H, Yan BS, Rojas M, Shebzukhov YV, Zhou H, Kobzik L, Higgins DE, Daly MJ, Bloom BR, Kramnik I. Ipr1 gene mediates innate immunity to tuberculosis. Nature. 2005 Apr 7; 434(7034):767-72. PMID: 15815631.
    View in: PubMed
  31. Boyartchuk V, Rojas M, Yan BS, Jobe O, Hurt N, Dorfman DM, Higgins DE, Dietrich WF, Kramnik I. The host resistance locus sst1 controls innate immunity to Listeria monocytogenes infection in immunodeficient mice. J Immunol. 2004 Oct 15; 173(8):5112-20. PMID: 15470055.
    View in: PubMed
  32. Kramnik I, Boyartchuk V. Immunity to intracellular pathogens as a complex genetic trait. Curr Opin Microbiol. 2002 Feb; 5(1):111-7. PMID: 11834379.
    View in: PubMed
  33. Kramnik I, Dietrich WF, Demant P, Bloom BR. Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2000 Jul 18; 97(15):8560-5. PMID: 10890913.
    View in: PubMed
  34. Alland D, Kramnik I, Weisbrod TR, Otsubo L, Cerny R, Miller LP, Jacobs WR, Bloom BR. Identification of differentially expressed mRNA in prokaryotic organisms by customized amplification libraries (DECAL): the effect of isoniazid on gene expression in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 1998 Oct 27; 95(22):13227-32. PMID: 9789070.
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  35. Kramnik I, Demant P, Bloom BB. Susceptibility to tuberculosis as a complex genetic trait: analysis using recombinant congenic strains of mice. Novartis Found Symp. 1998; 217:120-31; discussion 132-7. PMID: 9949805.
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  36. Barrera LF, Kramnik I, Skamene E, Radzioch D. I-A beta gene expression regulation in macrophages derived from mice susceptible or resistant to infection with M. bovis BCG. Mol Immunol. 1997 Mar; 34(4):343-55. PMID: 9244347.
    View in: PubMed
  37. Radzioch D, Kramnik I, Skamene E. Molecular mechanisms of natural resistance to mycobacterial infections. Circ Shock. 1994 Nov; 44(3):115-20. PMID: 7600634.
    View in: PubMed
  38. Barrera LF, Kramnik I, Skamene E, Radzioch D. Nitrite production by macrophages derived from BCG-resistant and -susceptible congenic mouse strains in response to IFN-gamma and infection with BCG. Immunology. 1994 Jul; 82(3):457-64. PMID: 7959883.
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  39. Kramnik I, Radzioch D, Skamene E. T-helper 1-like subset selection in Mycobacterium bovis bacillus Calmette-Guérin-infected resistant and susceptible mice. Immunology. 1994 Apr; 81(4):618-25. PMID: 8039813.
    View in: PubMed
  40. Apt AS, Avdienko VG, Nikonenko BV, Kramnik IB, Moroz AM, Skamene E. Distinct H-2 complex control of mortality, and immune responses to tuberculosis infection in virgin and BCG-vaccinated mice. Clin Exp Immunol. 1993 Nov; 94(2):322-9. PMID: 8222323.
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  41. Kramnik I, Skamene E, Radzioch D. Assessment of lymphokine profiles in activated lymphocytes by semiquantitative PCR. J Immunol Methods. 1993 Jun 18; 162(2):143-53. PMID: 7686197.
    View in: PubMed
  42. Avdienko VG, Kramnik IB, Apt AS, Litvinov VI. [The isolation and testing of syngeneic anti-idiotypic antibodies against antimycobacterial monoclonal antibodies]. Probl Tuberk. 1993; (1):47-50. PMID: 7687055.
    View in: PubMed
  43. Apt AS, Kramnik IB, Moroz AM. Regulation of T-cell proliferative responses by cells from solid lung tissue of M. tuberculosis-infected mice. Immunology. 1991 Jun; 73(2):173-9. PMID: 2071162.
    View in: PubMed
  44. Kramnik IG, Moroz AM, Apt AS. [Cellular mechanisms of suppression of T-lymphocyte proliferation by lung cells in experimental tuberculosis]. Biull Eksp Biol Med. 1990 Aug; 110(8):172-6. PMID: 1705456.
    View in: PubMed
  45. Kramnik IB, Apt AS, Moroz AM. [Suppression of immune response by lung cells in experimental tuberculosis]. Biull Eksp Biol Med. 1990 Jul; 110(7):77-80. PMID: 2145988.
    View in: PubMed
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