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Science 327 (5964): 466-469

Copyright © 2010 by the American Association for the Advancement of Science

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

Hannah E. Volkman,1,* Tamara C. Pozos,2,*,{dagger} John Zheng,2 J. Muse Davis,3 John F. Rawls,4,5 Lalita Ramakrishnan6,7,8,{ddagger}

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.

1 Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98155, USA.
2 Department of Pediatrics, University of Washington, Seattle, WA 98155, USA.
3 Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, GA 30322, USA.
4 Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
5 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
6 Department of Microbiology, University of Washington, Seattle, WA 98155, USA.
7 Department of Medicine, University of Washington, Seattle, WA 98155, USA.
8 Department of Immunology, University of Washington, Seattle, WA 98155, USA.

* These authors contributed equally to this work.

{dagger} Present address: Pediatric Infectious Diseases and Immunology, Children's Hospitals and Clinics of Minnesota, St. Paul, MN 55102, USA.

{ddagger} To whom correspondence should be addressed. E-mail: lalitar{at}u.washington.edu

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