Neutrophil elastase targets virulence factors of enterobacteria

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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Figure 1: Human neutrophil extract enriched in granule proteins (hNEGP) targets virulence proteins of Shigella.
Figure 2: NE degrades Shigella virulence proteins.
Figure 3: NE degrades secreted virulence proteins of Gram-negative bacterial pathogens.
Figure 4: Abrogation of NE permits Shigella to escape the phagosome of neutrophils.

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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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Correspondence to Arturo Zychlinsky.

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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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