The granuloma plays an important role in host defense against M. tuberculosis. The mechanisms that regulate the formation and maintenance of the tuberculous granuloma are, however, poorly understood. Chemokines and chemokine receptors play an essential role in cell migration in both physiological and pathophysiological states. Emerging evidence suggests a role for chemokine and chemokine receptors in regulating the granulomatous response during infection. M. tuberculosis has the ability to modulate chemokine and chemokine receptor expression in both in vitro and in vivo systems. Tumor necrosis factor-alpha (TNF-alpha) is essential for the control of tuberculosis, and is a potent regulator of chemokine expression and leukocyte trafficking. We have shown that neutralizing TNF-alpha in mice with persistent tuberculosis results in disease recrudescence associated with granuloma disorganization and diffuse cellular infiltration in the lungs. Based on these observations, we propose to test the hypotheses that: i) chemokines and chemokine receptors play an important role in orchestrating cell migration and granuloma formation in tuberculosis; and ii) TNF-alpha regulates the granulomatous response by directing the trafficking of immune cells at the site of infection via regulation of specific chemokines and chemokine receptors. Because of the importance of Type 1 T cells in host defense against M. tuberculosis, efforts will be focused on examining a subset of chemokines and receptors that can modulate migration of these T lymphocytes. Murine tuberculosis models, as well as immunohistochemical, laser microdissection, and realtime PCR techniques will be used to characterize the expression of these specific chemokines and receptors during tuberculous infection. Mice with disruption of specific chemokine receptor genes and ligand neutralizing reagents will be exploited to dissect specific chemokine network. Similar techniques, in conjunction with in vitro cell migration assays and the TNF-alpha neutralization model of murine reactivation tuberculosis, will be employed to evaluate the effects of TNF-alpha on the expression of specific chemokines and receptors, as well as on migration of T cells and monocytes during tuberculous infection. These studies should yield valuable information that will shed light on the roles of chemokines and receptors on cell migration, granuloma formation, and host defense in tuberculous infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071241-02
Application #
6615739
Study Section
Special Emphasis Panel (ZRG1-EVR (01))
Program Officer
Peavy, Hannah H
Project Start
2002-08-01
Project End
2007-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$522,759
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071036636
City
Bronx
State
NY
Country
United States
Zip Code
10461
Mattila, Joshua T; Ojo, Olabisi O; Kepka-Lenhart, Diane et al. (2013) Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol 191:773-84
Fallahi-Sichani, Mohammad; Flynn, JoAnne L; Linderman, Jennifer J et al. (2012) Differential risk of tuberculosis reactivation among anti-TNF therapies is due to drug binding kinetics and permeability. J Immunol 188:3169-78
Flynn, J L; Chan, J; Lin, P L (2011) Macrophages and control of granulomatous inflammation in tuberculosis. Mucosal Immunol 4:271-8
Russell, David G; Barry 3rd, Clifton E; Flynn, JoAnne L (2010) Tuberculosis: what we don't know can, and does, hurt us. Science 328:852-6
Lin, Philana Ling; Flynn, Joanne L (2010) Understanding latent tuberculosis: a moving target. J Immunol 185:15-22
Marino, Simeone; Myers, Amy; Flynn, JoAnne L et al. (2010) TNF and IL-10 are major factors in modulation of the phagocytic cell environment in lung and lymph node in tuberculosis: a next-generation two-compartmental model. J Theor Biol 265:586-98
Windish, Hillarie Plessner; Lin, P Ling; Mattila, Joshua T et al. (2009) Aberrant TGF-beta signaling reduces T regulatory cells in ICAM-1-deficient mice, increasing the inflammatory response to Mycobacterium tuberculosis. J Leukoc Biol 86:713-25
Maglione, Paul J; Chan, John (2009) How B cells shape the immune response against Mycobacterium tuberculosis. Eur J Immunol 39:676-86
Drumm, Joshua E; Mi, Kaixia; Bilder, Patrick et al. (2009) Mycobacterium tuberculosis universal stress protein Rv2623 regulates bacillary growth by ATP-Binding: requirement for establishing chronic persistent infection. PLoS Pathog 5:e1000460
Russell-Goldman, Eleanor; Xu, Jiayong; Wang, Xiaobing et al. (2008) A Mycobacterium tuberculosis Rpf double-knockout strain exhibits profound defects in reactivation from chronic tuberculosis and innate immunity phenotypes. Infect Immun 76:4269-81

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