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, Virology, Immunology & Microbiology, Boston University Chobanian & Avedisian School of Medicine
- Faculty, National Emerging Infectious Disease Lab, Boston University
- Member, Pulmonary Center, Boston University
- Member, Evans Center for Interdisciplinary Biomedical Research, Boston University
- Member, Genome Science Institute, Boston University
- Boston Medical Center
- Graduate Faculty (Primary Mentor of Grad Students), Boston University Chobanian & Avedisian School of Medicine, Graduate Medical Sciences
- Samara State Medical University, MD
- Russian Academy of Medical Sciences, PhD
- Published on 9/27/2023
Yabaji SM, Rukhlenko OS, Chatterjee S, Bhattacharya B, Wood E, Kasaikina M, Kholodenko BN, Gimelbrant AA, Kramnik I. Cell state transition analysis identifies interventions that improve control of Mycobacterium tuberculosis infection by susceptible macrophages. Sci Adv. 2023 Sep 29; 9(39):eadh4119. PMID: 37756395.
- Published on 7/23/2023
Klever AM, Alexander KA, Almeida D, Anderson MZ, Ball RL, Beamer G, Boggiatto P, Buikstra JE, Chandler B, Claeys TA, Concha AE, Converse PJ, Derbyshire KM, Dobos KM, Dupnik KM, Endsley JJ, Endsley MA, Fennelly K, Franco-Paredes C, Hagge DA, Hall-Stoodley L, Hayes D, Hirschfeld K, Hofman CA, Honda JR, Hull NM, Kramnik I, Lacourciere K, Lahiri R, Lamont EA, Larsen MH, Lemaire T, Lesellier S, Lee NR, Lowry CA, Mahfooz NS, McMichael TM, Merling MR, Miller MA, Nagajyothi JF, Nelson E, Nuermberger EL, Pena MT, Perea C, Podell BK, Pyle CJ, Quinn FD, Rajaram MVS, Mejia OR, Rothoff M, Sago SA, Salvador LCM, Simonson AW, Spencer JS, Sreevatsan S, Subbian S, Sunstrum J, Tobin DM, Vijayan KKV, Wright CTO, Robinson RT. The Many Hosts of Mycobacteria 9 (MHM9): A conference report. Tuberculosis (Edinb). 2023 Sep; 142:102377. PMID: 37531864.
- Published on 2/28/2023
Krug S, Prasad P, Xiao S, Lun S, Ruiz-Bedoya CA, Klunk M, Ordonez AA, Jain SK, Srikrishna G, Kramnik I, Bishai WR. Adjunctive Integrated Stress Response Inhibition Accelerates Tuberculosis Clearance in Mice. mBio. 2023 Apr 25; 14(2):e0349622. PMID: 36853048.
- Published on 2/10/2023
Yabaji SM, Rukhlenko OS, Chatterjee S, Bhattacharya B, Wood E, Kasaikina M, Kholodenko B, Gimelbrant AA, Kramnik I. Cell state transition analysis identifies interventions that improve control of M. tuberculosis infection by susceptible macrophages. bioRxiv. 2023 Feb 10. PMID: 36798271.
- Published on 5/26/2022
Rosenbloom R, Gavrish I, Tseng AE, Seidel K, Yabaji SM, Gertje HP, Huber BR, Kramnik I, Crossland NA. Progression and Dissemination of Pulmonary Mycobacterium Avium Infection in a Susceptible Immunocompetent Mouse Model. Int J Mol Sci. 2022 May 26; 23(11). PMID: 35682679.
- Published on 3/15/2022
Yabaji SM, Chatterjee S, Waligursky E, Gimelbrant A, Kramnik I. Medium throughput protocol for genome-based quantification of intracellular mycobacterial loads and macrophage survival during in vitro infection. STAR Protoc. 2022 06 17; 3(2):101241. PMID: 35310069.
- Published on 8/17/2021
Koyuncu D, Niazi MKK, Tavolara T, Abeijon C, Ginese ML, Liao Y, Mark C, Specht A, Gower AC, Restrepo BI, Gatti DM, Kramnik I, Gurcan M, Yener B, Beamer G. CXCL1: A new diagnostic biomarker for human tuberculosis discovered using Diversity Outbred mice. PLoS Pathog. 2021 08; 17(8):e1009773. PMID: 34403447.
- Published on 7/10/2021
Chatterjee S, Yabaji SM, Rukhlenko OS, Bhattacharya B, Waligurski E, Vallavoju N, Ray S, Kholodenko BN, Brown LE, Beeler AB, Ivanov AR, Kobzik L, Porco JA, Kramnik I. Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis. iScience. 2021 Aug 20; 24(8):102845. PMID: 34381970.
- Published on 6/21/2021
Ji DX, Witt KC, Kotov DI, Margolis SR, Louie A, Chevée V, Chen KJ, Gaidt MM, Dhaliwal HS, Lee AY, Nishimura SL, Zamboni DS, Kramnik I, Portnoy DA, Darwin KH, Vance RE. Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons. Elife. 2021 06 21; 10. PMID: 34151776.
- Published on 3/1/2021
Ordonez AA, Tucker EW, Anderson CJ, Carter CL, Ganatra S, Kaushal D, Kramnik I, Lin PL, Madigan CA, Mendez S, Rao J, Savic RM, Tobin DM, Walzl G, Wilkinson RJ, Lacourciere KA, Via LE, Jain SK. Visualizing the dynamics of tuberculosis pathology using molecular imaging. J Clin Invest. 2021 03 01; 131(5). PMID: 33645551.
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