Abstract
Shigellae cause bacillary dysentery, a bloody form of diarrhoea that affects almost 200 million people and causes nearly 2 million deaths per year1. Shigella invades the colonic mucosa, where it initiates an acute inflammation, rich in neutrophils, that initially contributes to tissue damage and eventually resolves the infection2. Neutrophils are phagocytic cells that kill microorganisms3,4 but it is unclear how neutrophils control pathogenic bacteria expressing virulence factors that manipulate host cells. In contrast to other cells, neutrophils prevent the escape of Shigella from phagocytic vacuoles in which the bacteria are killed5. Here we identify human neutrophil elastase (NE) as a key host defence protein: NE degrades Shigella virulence factors at a 1,000-fold lower concentration than that needed to degrade other bacterial proteins. In neutrophils in which NE is inactivated pharmacologically or genetically, Shigella escapes from phagosomes, increasing bacterial survival. NE also preferentially cleaves virulence factors of Salmonella and Yersinia. These findings establish NE as the first neutrophil factor that targets bacterial virulence proteins.
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References
Kotloff, K. L. et al. Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bull. World Health Org. 77, 651–666 (1999).
Perdomo, O. J. et al. Acute inflammation causes epithelial invasion and mucosal destruction in experimental shigellosis. J. Exp. Med. 180, 1307–1319 (1994).
Klebanoff, S. J. in Inflammation: Basic Principles and Clinical Correlates (eds Gallin, J. I. & Snyderman, R.) 721–768 (Lippincott Williams & Wilkins, Philadelphia, 1999).
Elsbach, P., Weiss, J. & Levy, O. in Inflammation: Basic Principles and Clinical Correlates (eds Gallin, J. J. & Snyderman, R.) 801–817 (Lippincott Williams & Wilkins, Philadelphia, 1999).
Mandic-Mulec, I., Weiss, J. & Zychlinsky, A. Shigella flexneri is trapped in polymorphnuclear leukocyte vacuoles and efficiently killed. Infect. Immun. 65, 110–115 (1997).
Hale, T. L. Genetic basis of virulence in Shigella species. Microbiol. Rev. 55, 206–224 (1991).
Cornelis, G. R. & Van Gijsegem, F. Assembly and function of type III secretory systems. Annu. Rev. Microbiol. 54, 735–774 (2000).
Suzuki, T., Lett, M. C. & Sasakawa, C. Extracellular transport of VirG protein in Shigella. J. Biol. Chem. 270, 30874–30880 (1995).
Bahrani, F. K., Sansonetti, P. J. & Parsot, C. Secretion of Ipa proteins by Shigella flexneri: inducer molecules and kinetics of activation. Infect. Immun. 65, 4005–4010 (1997).
Owen, C. A. & Campbell, E. J. The cell biology of leukocyte-mediated proteolysis. J. Leukoc. Biol. 65, 137–150 (1999).
Campbell, E. J., Silverman, E. K. & Campbell, M. A. Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity. J. Immunol. 143, 2961–2968 (1989).
Veale, C. A. et al. Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase. J. Med. Chem. 40, 3173–3181 (1997).
Wright, C. D., Kennedy, J. A., Zitnik, R. J. & Kashem, M. A. Inhibition of murine neutrophil serine proteinases by human and murine secretory leukocyte protease inhibitor. Biochem. Biophys. Res. Commun. 254, 614–617 (1999).
Belaaouaj, A., Kim, K. S. & Shapiro, S. D. Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase. Science 289, 1185–1188 (2000).
Panyutich, A., Shi, J., Boutz, P. L., Zhao, C. & Ganz, T. Porcine polymorphonuclear leukocytes generate extracellular microbicidal activity by elastase-mediated activation of secreted proprotegrins. Infect. Immun. 65, 978–985 (1997).
Tamano, K. et al. Supramolecular structure of the Shigella type III secretion machinery: the needle part is changeable in length and essential for delivery of effectors. EMBO J. 19, 3876–3887 (2000).
Blocker, A. et al. Structure and composition of the Shigella flexneri ‘needle complex’, a part of its type III secreton. Mol. Microbiol. 39, 652–663 (2001).
Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103 (2001).
Eisenhauer, P. B., Harwig, S. S. & Lehrer, R. I. Cryptdins: Antimicrobial defensins of the murine small intestine. Infect. Immun. 60, 3556–3565 (1992).
Francois, M., Le Cabec, V., Dupont, M. A., Sansonetti, P. J. & Maridonneau-Parini, I. Induction of necrosis in human neutrophils by Shigella flexneri requires type III secretion, IpaB and IpaC invasins, and actin polymerization. Infect. Immun. 68, 1289–1296 (2000).
Pallen, M. J., Dougan, G. & Frankel, G. Coiled-coil domains in proteins secreted by type III secretion systems. Mol. Microbiol. 25, 423–425 (1997).
Miao, E. A. et al. leucine-rich repeat proteins are targeted to the SPI1 and SPI2 type III secretion systems. Mol. Microbiol. 34, 850–864 (1999).
Menard, R., Sansonetti, P. J. & Parsot, C. Nonpolar mutagenesis of the ipa genes defines IpaB, IpaC, and IpaD as effectors of Shigella flexneri entry into epithelial cells. J. Bacteriol. 175, 5899–5906 (1993).
Weiss, J., Elsbach, P., Olsson, I. & Odeberg, H. Purification and characterization of a potent bactericidal and membrane active protein from the granules of human polymorphonucelar leukocytes. J. Biol. Chem. 253, 2664–2672 (1978).
Lee, V. T. & Schneewind, O. Type III machines of pathogenic Yersiniae secrete virulence factors into the extracellular milieu. Mol. Microbiol. 31, 1619–1629 (1999).
Ginocchio, C. C. & Galan, J. E. Functional conservation among members of the Salmonella typhimurium InvA family of proteins. Infect. Immun. 63, 729–732 (1995).
Huang, Y. I. et al. Effect of trifluoromethyl ketone-based elastase inhibitors on neutrophil function in vitro. J. Leukoc. Biol. 64, 322–330 (1998).
Weiss, J., Kao, L., Victor, M. & Elsbach, P. Oxygen-independent intracellular and oxygen-dependent extracellular killing of Escherichia coli S15 by human polymorphonuclear leukocytes. J. Clin. Invest. 76, 206–212 (1985).
Sansonetti, P. J., Arondel, J., Huerre, M., Harada, A. & Matsushima, K. Interleukin-8 controls bacterial transepithelial translocation at the cost of epithelial destruction in experimental shigellosis. Infect. Immun. 67, 1471–1480 (1999).
Gbarah, A. et al. Shigella flexneri transformants expressing type 1 (mannose-specific) fimbriae bind to, activate, and are killed by phagocytic cells. Infect. Immun. 61, 1687–1693 (1993).
Acknowledgements
We thank D. Weiss and C. Scharff for critical reading of the manuscript, T. Nubert and D. Wu for performing MS analysis, and staff of the Rockefeller University EM facility. A.Z. is a recipient of the Irma T. Hirschl Trust Career Scientist Award. Financial support from the National Institutes of Health is acknowledged.
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Weinrauch, Y., Drujan, D., Shapiro, S. et al. Neutrophil elastase targets virulence factors of enterobacteria. Nature 417, 91–94 (2002). https://doi.org/10.1038/417091a
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DOI: https://doi.org/10.1038/417091a
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