Publication Date:
2009-12-17
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125975/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125975/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Volkman, Hannah E -- Pozos, Tamara C -- Zheng, John -- Davis, J Muse -- Rawls, John F -- Ramakrishnan, Lalita -- F32 DK062675/DK/NIDDK NIH HHS/ -- F32 DK062675-02/DK/NIDDK NIH HHS/ -- F32 DK062675-03/DK/NIDDK NIH HHS/ -- K01 DK073695/DK/NIDDK NIH HHS/ -- K01 DK073695-01/DK/NIDDK NIH HHS/ -- K01 DK073695-02/DK/NIDDK NIH HHS/ -- K01 DK073695-03/DK/NIDDK NIH HHS/ -- K01 DK073695-04/DK/NIDDK NIH HHS/ -- R01 AI036396/AI/NIAID NIH HHS/ -- R01 AI036396-19/AI/NIAID NIH HHS/ -- R01 AI054503/AI/NIAID NIH HHS/ -- R01 AI054503-09/AI/NIAID NIH HHS/ -- R01 DK081426/DK/NIDDK NIH HHS/ -- R01 DK081426-01/DK/NIDDK NIH HHS/ -- R01 DK081426-02/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2010 Jan 22;327(5964):466-9. doi: 10.1126/science.1179663. Epub 2009 Dec 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98155, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20007864" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, Bacterial/genetics/*metabolism
;
Bacterial Proteins/genetics/*metabolism
;
Disease Models, Animal
;
Embryo, Nonmammalian/microbiology
;
Enzyme Induction
;
Epithelial Cells/*enzymology
;
Granuloma/metabolism/*microbiology
;
Macrophages/microbiology/physiology
;
Matrix Metalloproteinase 9/genetics/*metabolism
;
Mycobacterium Infections, Nontuberculous/*microbiology
;
Mycobacterium marinum/growth & development/metabolism/*pathogenicity
;
Mycobacterium tuberculosis/genetics/pathogenicity
;
Oligoribonucleotides, Antisense
;
Recombinant Proteins/metabolism
;
Tuberculosis/*microbiology
;
Virulence Factors/genetics/*metabolism
;
Zebrafish/embryology
;
Zebrafish Proteins/genetics/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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