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.
- Associate Professor, Microbiology, Boston University School of Medicine
- Boston Medical Center
- Faculty, National Emerging Infectious Disease Lab, Boston University
- Member, Pulmonary Center, Boston University
- Member, Evans Center for Interdisciplinary Biomedical Research, Boston University
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Graduate Medical Sciences
- Member, Genome Science Institute, Boston University
- Samara State Medical University, MD
- Russian Academy of Medical Sciences, PhD
- Published on 5/1/2020
Ji DX, Yamashiro LH, Chen KJ, Mukaida N, Kramnik I, Darwin KH, Vance RE. Publisher Correction: Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra. Nat Microbiol. 2020 May; 5(5):777. PMID: 32300234.
- Published on 4/15/2020
Kurtz SL, Rossi AP, Beamer GL, Gatti DM, Kramnik I, Elkins KL. The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection. mSphere. 2020 Apr 15; 5(2). PMID: 32295871.
- Published on 10/14/2019
Ji DX, Yamashiro LH, Chen KJ, Mukaida N, Kramnik I, Darwin KH, Vance RE. Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra. Nat Microbiol. 2019 12; 4(12):2128-2135. PMID: 31611644.
- Published on 4/23/2019
Carow B, Hauling T, Qian X, Kramnik I, Nilsson M, Rottenberg ME. Spatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma. Nat Commun. 2019 04 23; 10(1):1823. PMID: 31015452.
- Published on 12/26/2017
Gregory DJ, Kramnik I, Kobzik L. Protection of macrophages from intracellular pathogens by miR-182-5p mimic-a gene expression meta-analysis approach. FEBS J. 2018 01; 285(2):244-260. PMID: 29197182.
- Published on 8/15/2017
Coleman FT, Blahna MT, Kamata H, Yamamoto K, Zabinski MC, Kramnik I, Wilson AA, Kotton DN, Quinton LJ, Jones MR, Pelton SI, Mizgerd JP. Capacity of Pneumococci to Activate Macrophage Nuclear Factor ?B: Influence on Necroptosis and Pneumonia Severity. J Infect Dis. 2017 Aug 15; 216(4):425-435. PMID: 28368460.
- Published on 2/1/2017
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. 2017 Feb 01; 195(3):369-382. PMID: 27858493.
- Published on 11/28/2016
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 11 28; 6:37793. PMID: 27892960.
- Published on 4/18/2016
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.
- Published on 11/5/2015
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.
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