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* Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208; and
Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294
A striking feature of pulmonary infection with the Gram-negative intracellular bacterium Francisella tularensis, a category A biological threat agent, is an intense accumulation of inflammatory cells, particularly neutrophils and macrophages, at sites of bacterial replication. Given the essential role played by host matrix metalloproteinases (MMPs) in modulating leukocyte recruitment and the potentially indiscriminate destructive capacity of these cells, we investigated whether MMP-9, an important member of this protease family released by neutrophils and activated macrophages, plays a role in the pathogenesis of respiratory tularemia. We found that F. tularensis induced expression of MMP-9 in FVB/NJ mice and that the action of this protease is associated with higher bacterial burdens in pulmonary and extrapulmonary tissues, development of more extensive histopathology predominated by neutrophils, and increased morbidity and mortality compared with mice lacking MMP-9 (MMP-9–/–). Moreover, MMP-9–/– mice were able to resolve infection with either the virulence-attenuated type B (live vaccine strain) or the highly virulent type A (SchuS4) strain of F. tularensis. Disease resolution was accompanied by diminished leukocyte recruitment and reductions in both bacterial burden and proinflammatory cytokine production. Notably, neutrophilic infiltrates were significantly reduced in MMP-9–/– mice, owing perhaps to limited release of Pro-Gly-Pro, a potent neutrophil chemotactic tripeptide released from extracellular matrix through the action of MMP-9. Collectively, these results suggest that MMP-9 activity plays a central role in modulating the clinical course and severity of respiratory tularemia and identifies MMPs as novel targets for therapeutic intervention as a means of modulating neutrophil recruitment.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by U.S. Public Health Service Grants PO1 AI056320 (to T.J.S. and D.W.M.), HL077783-01A2 (to J.E.B.), HL68806 (to J.E.B.), and Cystic Fibrosis Foundation R464-CR02 (to J.E.B.). Funds for the purchase of mass spectrometers and the operation of the Mass Spectrometry Shared Facility came from the following National Institutes of Health grants to the University of Alabama at Birmingham: S10 RR19231, P30 CA13148, P50 AT00477, U54 CA100949, P30 AR050948, and P30 DK74038.
2 Address correspondence and reprint requests to Dr. Timothy J. Sellati, Center for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, MC151, ME205B, Albany, NY 12208-3479.
3 Abbreviations used in this paper: LVS, live vaccine strain; PI, postinfection; MMP, matrix metalloproteinase; ECM, extracellular matrix; PGP, Pro-Gly-Pro; MH, Mueller-Hinton; i.n., intranasal; BAL, bronchoalveolar lavage; BALF, BAL fluid; MTD, median time to death; ESI-LC-MS/MS, electron spray ionization-liquid chromatography-mass spectrometry/mass spectrometry.
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