Tuberculous Granuloma Induction Via Interaction of a Bacterial Secreted Protein with Host Epithelium

Overview

Journal Science

Specialty Science

Date 2009 Dec 17

PMID 20007864

Citations 231

Authors

Hannah E Volkman

Tamara C Pozos

John Zheng

J Muse Davis

John F Rawls

Lalita Ramakrishnan

Affiliations

Soon will be listed here.

Abstract

Granulomas, organized aggregates of immune cells, are a hallmark of tuberculosis and have traditionally been thought to restrict mycobacterial growth. However, analysis of Mycobacterium marinum in zebrafish has shown that the early granuloma facilitates mycobacterial growth; uninfected macrophages are recruited to the granuloma where they are productively infected by M. marinum. Here, we identified the molecular mechanism by which mycobacteria induce granulomas: The bacterial secreted protein 6-kD early secreted antigenic target (ESAT-6), which has long been implicated in virulence, induced matrix metalloproteinase-9 (MMP9) in epithelial cells neighboring infected macrophages. MMP9 enhanced recruitment of macrophages, which contributed to nascent granuloma maturation and bacterial growth. Disruption of MMP9 function attenuated granuloma formation and bacterial growth. Thus, interception of epithelial MMP9 production could hold promise as a host-targeting tuberculosis therapy.

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References

Chang J, Wysocki A, MOSKOWITZ N, Zhang Y, Rom W . Effect of Mycobacterium tuberculosis and its components on macrophages and the release of matrix metalloproteinases. Thorax. 1996; 51(3):306-11. PMC: 1090645. DOI: 10.1136/thx.51.3.306. View

Taylor J, Hattle J, Dreitz S, Troudt J, Izzo L, Basaraba R . Role for matrix metalloproteinase 9 in granuloma formation during pulmonary Mycobacterium tuberculosis infection. Infect Immun. 2006; 74(11):6135-44. PMC: 1695484. DOI: 10.1128/IAI.02048-05. View

Stanley S, Raghavan S, Hwang W, Cox J . Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. Proc Natl Acad Sci U S A. 2003; 100(22):13001-6. PMC: 240734. DOI: 10.1073/pnas.2235593100. View

Simeone R, Bottai D, Brosch R . ESX/type VII secretion systems and their role in host-pathogen interaction. Curr Opin Microbiol. 2009; 12(1):4-10. DOI: 10.1016/j.mib.2008.11.003. View

Hagedorn M, Rohde K, Russell D, Soldati T . Infection by tubercular mycobacteria is spread by nonlytic ejection from their amoeba hosts. Science. 2009; 323(5922):1729-33. PMC: 2770343. DOI: 10.1126/science.1169381. View

Clay H, Davis J, Beery D, Huttenlocher A, Lyons S, Ramakrishnan L . Dichotomous role of the macrophage in early Mycobacterium marinum infection of the zebrafish. Cell Host Microbe. 2007; 2(1):29-39. PMC: 3115716. DOI: 10.1016/j.chom.2007.06.004. View

Volkman H, Clay H, Beery D, Chang J, Sherman D, Ramakrishnan L . Tuberculous granuloma formation is enhanced by a mycobacterium virulence determinant. PLoS Biol. 2004; 2(11):e367. PMC: 524251. DOI: 10.1371/journal.pbio.0020367. View

Shi S, Nathan C, Schnappinger D, Drenkow J, Fuortes M, Block E . MyD88 primes macrophages for full-scale activation by interferon-gamma yet mediates few responses to Mycobacterium tuberculosis. J Exp Med. 2003; 198(7):987-97. PMC: 2194223. DOI: 10.1084/jem.20030603. View

Hsu T, Hingley-Wilson S, Chen B, Chen M, Dai A, Morin P . The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue. Proc Natl Acad Sci U S A. 2003; 100(21):12420-5. PMC: 218773. DOI: 10.1073/pnas.1635213100. View

10.

Wolf A, Linas B, Trevejo-Nunez G, Kincaid E, Tamura T, Takatsu K . Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. J Immunol. 2007; 179(4):2509-19. DOI: 10.4049/jimmunol.179.4.2509. View

11.

Zhu X, Price N, Gilman R, Recarvarren S, Friedland J . Multinucleate giant cells release functionally unopposed matrix metalloproteinase-9 in vitro and in vivo. J Infect Dis. 2007; 196(7):1076-9. DOI: 10.1086/521030. View

12.

Champion P, Cox J . Protein secretion systems in Mycobacteria. Cell Microbiol. 2007; 9(6):1376-84. DOI: 10.1111/j.1462-5822.2007.00943.x. View

13.

Le Guellec D, Morvan-Dubois G, Sire J . Skin development in bony fish with particular emphasis on collagen deposition in the dermis of the zebrafish (Danio rerio). Int J Dev Biol. 2004; 48(2-3):217-31. DOI: 10.1387/ijdb.15272388. View

14.

Ulrichs T, Kaufmann S . New insights into the function of granulomas in human tuberculosis. J Pathol. 2005; 208(2):261-9. DOI: 10.1002/path.1906. View

15.

Adams D . The granulomatous inflammatory response. A review. Am J Pathol. 1976; 84(1):164-92. PMC: 2032357. View

16.

Sheen P, OKane C, Chaudhary K, Tovar M, Santillan C, Sosa J . High MMP-9 activity characterises pleural tuberculosis correlating with granuloma formation. Eur Respir J. 2008; 33(1):134-41. DOI: 10.1183/09031936.00127807. View

17.

Koo I, Wang C, Raghavan S, Morisaki J, Cox J, Brown E . ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection. Cell Microbiol. 2008; 10(9):1866-78. PMC: 2574867. DOI: 10.1111/j.1462-5822.2008.01177.x. View

18.

Greenlee K, Werb Z, Kheradmand F . Matrix metalloproteinases in lung: multiple, multifarious, and multifaceted. Physiol Rev. 2007; 87(1):69-98. PMC: 2656382. DOI: 10.1152/physrev.00022.2006. View

19.

Davis J, Ramakrishnan L . The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell. 2009; 136(1):37-49. PMC: 3134310. DOI: 10.1016/j.cell.2008.11.014. View

20.

Russell D . Who puts the tubercle in tuberculosis?. Nat Rev Microbiol. 2006; 5(1):39-47. DOI: 10.1038/nrmicro1538. View