title: IgG protease Mac/IdeS is not essential for phagocyte resistance or mouse virulence of M1T1 group A Streptococcus.
abstract: The Mac/IdeS protein of group A Streptococcus (GAS) is a secreted cysteine protease with cleavage specificity for IgG and is highly expressed in the GAS serotype M1T1 clone, which is the serotype most frequently isolated from patients with life-threatening invasive infections. While studies of Mac/IdeS with recombinant protein have shown that the protein can potentially prevent opsonophagocytosis of GAS by neutrophils, the role of the protein in immune evasion as physiologically produced by the living organism has not been studied. Here we examined the contribution of Mac/IdeS to invasive GAS disease by generating a mutant lacking Mac/IdeS in the hyperinvasive M1T1 background. While Mac/IdeS was highly expressed and proteolytically active in the hyperinvasive strain, elimination of the bacterial protease did not significantly influence GAS phagocytic uptake, oxidative-burst induction, cathelicidin sensitivity, resistance to neutrophil or macrophage killing, or pathogenicity in pre- or postimmune mouse infectious challenges. We conclude that in the highly virulent M1T1 background, Mac/IdeS is not essential for either phagocyte resistance or virulence. Given the conservation of Mac/IdeS and homologues across GAS strains, it is possible that Mac/IdeS serves another important function in GAS ecology or contributes to virulence in other strain backgrounds.
  
  
  OBJECTIVE
  Group A Streptococcus (GAS) causes human infections ranging from strep throat to life-threatening conditions such as flesh-eating disease and toxic shock syndrome. Common disease-associated clones of GAS can cause both mild and severe infections because of a characteristic mutation and subsequent change in the expression of several genes that develops under host immune selection. One of these genes encodes Mac/IdeS, a protease that has been shown to cleave antibodies important to the immune defense system. In this study, we found that while Mac/IdeS is highly expressed in hypervirulent GAS, it does not significantly contribute to the ability of the bacteria to survive white blood cell killing or produce invasive infection in the mouse. These data underscore the importance of correlating studies on virulence factor function with physiologic expression levels and the complexity of streptococcal pathogenesis and contribute to our overall understanding of how GAS causes disease.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA. okumura@oxy.edu
authors.forename: Cheryl Y M
authors.initials: CY
authors.lastname: Okumura
authors.forename: Ericka L
authors.initials: EL
authors.lastname: Anderson
authors.forename: Simon
authors.initials: S
authors.lastname: Döhrmann
authors.forename: Dan N
authors.initials: DN
authors.lastname: Tran
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.forename: Ulrich
authors.initials: U
authors.lastname: von Pawel-Rammingen
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018920:Coculture Techniques; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D008297:Male; D051379:Mice; D050296:Microbial Viability; D010586:Phagocytes / Q000382:microbiology*; D010587:Phagocytosis; D059748:Proteolysis; D013290:Streptococcal Infections / Q000382:microbiology / Q000473:pathology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D007074:Immunoglobulin G; C442815:Mac-1-like protein, Streptococcus; D037521:Virulence Factors
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