1. Skirball Institute and Department of Microbiology, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA
2. Department of Medicine, Pulmonary and Critical Care, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Departments of Internal Medicine and Microbiology, The Inflammation Program, University of Iowa College of Medicine, Iowa City Veterans' Administration Medical Center, 200 Hawkins Drive, Iowa City, Iowa 52242, USA
4. Max Planck Institute for Infection Biology, Schumannstrasse 21/22, Campus Charité Mitte, Berlin D-10117, Germany

Correspondence to: Arturo Zychlinsky^1,4 Correspondence and requests for materials should be addressed to A.Z. (e-mail: Email: zychlinsky@mpiib-berlin.mpg.de).

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 microorganisms^{3, 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.