Group A Streptococcal M1 Protein Provides Resistance against the Antimicrobial Activity of Histones

• Type of Material: Article
• Authors: Simon Dohrmann, University of California San Diego; Christopher LaRock, Emory University; Ericka L. Anderson, University of California San Diego; Jason N. Cole, University of California San Diego; Brinda Ryali, University of California San Diego; Chelsea Stewart, University of California San Diego; Poochit Nonejuie, University of California San Diego; Joe Pogliano, University of California San Diego; Ross Corriden, University of California San Diego; Partho Ghosh, University of California San Diego; Victor Nizet, University of California San Diego
• Language: English
• Date: 2017-02-21
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2017.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/srep43039
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 7
• Issue: 1
• Start Page: 1
• End Page: 11
• Keywords: MECHANISMS; BACTERIAL PATHOGENS; Multidisciplinary Sciences; VIRULENCE; Science & Technology - Other Topics; MOLECULES; LYSINE-RICH HISTONES; DIFFERENTIAL-MODE; STAPHYLOCOCCUS-AUREUS; NEUTROPHILS; COILED-COIL; EXTRACELLULAR TRAP FORMATION; Science & Technology
• Research Categories: Health Sciences, Pharmacology; Chemistry, Biochemistry

Abstract

Histones are essential elements of chromatin structure and gene regulation in eukaryotes. An unexpected attribute of these nuclear proteins is their antimicrobial activity. A framework for histone release and function in host defense in vivo was revealed with the discovery of neutrophil extracellular traps, a specialized cell death process in which DNA-based structures containing histones are extruded to ensnare and kill bacteria. Investigating the susceptibility of various Gram-positive pathogens to histones, we found high-level resistance by one leading human pathogen, group A Streptococcus (GAS). A screen of isogenic mutants revealed that the highly surface-expressed M1 protein, a classical GAS virulence factor, was required for high-level histone resistance. Biochemical and microscopic analyses revealed that the N-terminal domain of M1 protein binds and inactivates histones before they reach their cell wall target of action. This finding illustrates a new pathogenic function for this classic GAS virulence factor, and highlights a potential innate immune evasion strategy that may be employed by other bacterial pathogens.