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

• 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
• Journal Title: Scientific Reports
• Volume: Volume 7, Number 1
• Publisher: Nature Research (part of Springer Nature): Fully open access journals | 2017-02-21, Pages 1-11
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/srep43039
• Subjects: Health Sciences, Pharmacology; Chemistry, Biochemistry
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; EXTRACELLULAR TRAP FORMATION; LYSINE-RICH HISTONES; STAPHYLOCOCCUS-AUREUS; COILED-COIL; BACTERIAL PATHOGENS; DIFFERENTIAL-MODE; NEUTROPHILS; MECHANISMS; MOLECULES; VIRULENCE

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.