title: D-alanylation of teichoic acids promotes group a streptococcus antimicrobial peptide resistance, neutrophil survival, and epithelial cell invasion.
abstract: Group A streptococcus (GAS) is a leading cause of severe, invasive human infections, including necrotizing fasciitis and toxic shock syndrome. An important element of the mammalian innate defense system against invasive bacterial infections such as GAS is the production of antimicrobial peptides (AMPs) such as cathelicidins. In this study, we identify a specific GAS phenotype that confers resistance to host AMPs. Allelic replacement of the dltA gene encoding d-alanine-d-alanyl carrier protein ligase in an invasive serotype M1 GAS isolate led to loss of teichoic acid d-alanylation and an increase in net negative charge on the bacterial surface. Compared to the wild-type (WT) parent strain, the GAS DeltadltA mutant exhibited increased susceptibility to AMP and lysozyme killing and to acidic pH. While phagocytic uptake of WT and DeltadltA mutants by human neutrophils was equivalent, neutrophil-mediated killing of the DeltadltA strain was greatly accelerated. Furthermore, we observed the DeltadltA mutant to be diminished in its ability to adhere to and invade cultured human pharyngeal epithelial cells, a likely proximal step in the pathogenesis of invasive infection. Thus, teichoic acid d-alanylation may contribute in multiple ways to the propensity of invasive GAS to bypass mucosal defenses and produce systemic infection.
authors.affiliation: Division of Pediatric Infectious Diseases, University of California, San Diego School of Medicine, Cellular & Molecular Medicine East, Room 1066, 9500 Gilman Drive, Mail Code 0687, La Jolla, CA 92093-0687, USA.
authors.forename: Sascha A
authors.initials: SA
authors.lastname: Kristian
authors.forename: Vivekanand
authors.initials: V
authors.lastname: Datta
authors.forename: Christopher
authors.initials: C
authors.lastname: Weidenmaier
authors.forename: Rita
authors.initials: R
authors.lastname: Kansal
authors.forename: Iris
authors.initials: I
authors.lastname: Fedtke
authors.forename: Andreas
authors.initials: A
authors.lastname: Peschel
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000409:Alanine / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001422:Bacterial Adhesion / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000382:microbiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009113:Muramidase / Q000378:metabolism; D016296:Mutagenesis; D009504:Neutrophils / Q000166:cytology / Q000382:microbiology*; D009876:Operon / Q000502:physiology; D010587:Phagocytosis / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000472:pathogenicity; D013682:Teichoic Acids / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics
chemical_list: D023181:Antimicrobial Cationic Peptides; D013682:Teichoic Acids; D037521:Virulence Factors; D009113:Muramidase; D000409:Alanine