title: Group A Streptococcal M1 Protein Provides Resistance against the Antimicrobial Activity of Histones.
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.
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Simon
authors.initials: S
authors.lastname: Döhrmann
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: LaRock
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ericka L
authors.initials: EL
authors.lastname: Anderson
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Brinda
authors.initials: B
authors.lastname: Ryali
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Department of Biological Sciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Poochit
authors.initials: P
authors.lastname: Nonejuie
authors.affiliation: Department of Biological Sciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Joe
authors.initials: J
authors.lastname: Pogliano
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.|Department of Pharmacology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ross
authors.initials: R
authors.lastname: Corriden
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Partho
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.|Department of Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.|Rady Children's Hospital, San Diego, California, United States of America.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism / Q000502:physiology*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D013290:Streptococcal Infections / Q000378:metabolism / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D037521:Virulence Factors / Q000378:metabolism / Q000502:physiology
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D006657:Histones; D037521:Virulence Factors; C014689:streptococcal M protein