Detoxification of reactive oxygen species by the hyaluronic acid capsule of group A Streptococcus

• Type of Material: Article
• Authors: Shyra Wilde, Emory University; Ananya Dash, Emory University; Anders Johnson, Emory University; Kialani Mackey, Occidental College; Cheryl Y. M. Okumura, Occidental College; Christopher LaRock, Emory University
• Language: English
• Date: 2023-10-24
• Publisher: AMER SOC MICROBIOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Wilde et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/iai.00258-23
• Title of Journal or Parent Work: INFECTION AND IMMUNITY
• Volume: 91
• Issue: 11
• Start Page: e0025823
• End Page: e0025823
• Grant/Funding Information: This work was supported by US National Institutes of Health grants (AI130223 and AI153071 to C.N.L.) and the American Heart Association (17GRNT33410851 to C.O.). C.N.L. is a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases.
• Keywords: MODEL; INFECTION; Streptococcus pyogenes; PROTEASE; interleukins; SUPEROXIDE; oxygen radicals; capsule; MUTANTS; MACROPHAGES; VIRULENCE; Life Sciences & Biomedicine; group A Streptococcus; Immunology; Infectious Diseases; COLONIZATION; EXPRESSION; Science & Technology; PEROXIDE RESISTANCE
• Research Categories: Biology, Virology; Health Sciences, Immunology

Abstract

The pro-inflammatory cytokine IL-6 regulates antimicrobial responses that are broadly crucial in the defense against infection. Our prior work shows that IL-6 promotes the killing of the M4 serotype group A Streptococcus (GAS) but does not impact the globally disseminated M1T1 serotype associated with invasive infections. Using in vitro and in vivo infection models, we show that IL-6 induces phagocyte reactive oxygen species (ROS) that are responsible for the differential susceptibility of M4 and M1T1 GAS to IL-6-mediated defenses. Clinical isolates naturally deficient in capsule, or M1T1 strains deficient in capsule production, are sensitive to this ROS killing. The GAS capsule is made of hyaluronic acid, an antioxidant that detoxifies ROS and can protect acapsular M4 GAS when added exogenously. During in vitro interactions with macrophages and neutrophils, acapsular GAS can also be rescued with the antioxidant N-acetylcysteine, suggesting this is a major virulence contribution of the capsule. In an intradermal infection model with gp91phox -/- (chronic granulomatous disease [CGD]) mice, phagocyte ROS production had a modest effect on bacterial proliferation and the cytokine response but significantly limited the size of the bacterial lesion in the skin. These data suggest that the capsule broadly provides enhanced resistance to phagocyte ROS but is not essential for invasive infection. Since capsule-deficient strains are observed across several GAS serotypes and are competent for transmission and both mild and invasive infections, additional host or microbe factors may contribute to ROS detoxification during GAS infections.