title: Hyaluronan breakdown contributes to immune defense against group A Streptococcus.
abstract: Group A Streptococcus (GAS) commonly infects human skin and occasionally causes severe and life-threatening invasive diseases. The hyaluronan (HA) capsule of GAS has been proposed to protect GAS from host defense by mimicking endogenous HA, a large and abundant glycosaminoglycan in the skin. However, HA is degraded during tissue injury, and the functions of short-chain HA that is generated during infection have not been studied. To examine the impact of the molecular mass of HA on GAS infection, we established infection models in vitro and in vivo in which the size of HA was defined by enzymatic digestion or custom synthesis. We discovered that conversion of high molecular mass HA to low molecular mass HA facilitated GAS phagocytosis by macrophages and limited the severity of infection in mice. In contrast, native high molecular mass HA significantly impaired internalization by macrophages and increased GAS survival in murine blood. Thus, our data demonstrate that GAS virulence can be influenced by the size of HA derived from both the bacterium and host and suggest that high molecular mass HA facilitates GAS deep tissue infections, whereas the generation of short-chain HA can be protective.
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, San Diego, La Jolla, California 92093.
authors.forename: Nina N
authors.initials: NN
authors.lastname: Schommer
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, San Diego, La Jolla, California 92093.
authors.forename: Jun
authors.initials: J
authors.lastname: Muto
authors.affiliation: Division of Pharmacology and Drug Discovery, Department of Pediatrics, and University of California, San Diego, La Jolla, California 92093; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, San Diego, La Jolla, California 92093; Division of Pharmacology and Drug Discovery, Department of Pediatrics, and University of California, San Diego, La Jolla, California 92093. Electronic address: rgallo@ucsd.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
mesh_terms: D000818:Animals; D016667:Bacterial Capsules / Q000276:immunology*; D002460:Cell Line; D006801:Humans; D006820:Hyaluronic Acid / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010587:Phagocytosis; D017192:Skin Diseases, Bacterial / Q000276:immunology* / Q000473:pathology; D013290:Streptococcal Infections / Q000276:immunology* / Q000473:pathology; D013297:Streptococcus pyogenes / Q000276:immunology*
chemical_list: D006820:Hyaluronic Acid
keywords: Hyaluronan; Hyaluronidase; Innate Immunity; Skin; Streptococcus pyogenes (S. pyogenes)