M proteins of group A Streptococcus bind hyaluronic acid via arginine–arginine/serine–arginine motifs

• Published in: The FASEB journal 2024-10, Vol.38 (20), p.e70123-n/a
• Main Authors: McEwan, Tahnee B.‐D., De Oliveira, David M. P., Stares, Emily K., Hartley‐Tassell, Lauren E., Day, Christopher J., Proctor, Emma‐Jayne, Nizet, Victor, Walker, Mark J., Jennings, Michael P., Sluyter, Ronald, Sanderson‐Smith, Martina L.
• Format: Article
• Language: English
• Subjects: adherence; Amino Acid Motifs; Antigens, Bacterial - metabolism; Arginine - metabolism; Bacterial Adhesion; Bacterial Outer Membrane Proteins - metabolism; binding motif; Carrier Proteins - metabolism; glycosaminoglycan; Humans; Hyaluronic Acid - metabolism; Keratinocytes - metabolism; Keratinocytes - microbiology; M protein; mutagenesis; Protein Binding; Serine - metabolism; Streptococcal Infections - metabolism; Streptococcal Infections - microbiology; Streptococcus pyogenes; Streptococcus pyogenes - metabolism; surface plasmon resonance; Wound Healing
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202401301R

Tissue injury, including extracellular matrix (ECM) degradation, is a hallmark of group A Streptococcus (GAS) skin infection and is partially mediated by M proteins which possess lectin‐like properties. Hyaluronic acid is a glycosaminoglycan enriched in the cutaneous ECM, yet an interaction with M proteins has yet to be explored. This study revealed that hyaluronic acid binding was conserved across phylogenetically diverse M proteins, mediated by RR/SR motifs predominantly localized in the C repeat region. Keratinocyte wound healing was decreased through the recruitment of hyaluronic acid by M proteins in an M type‐specific manner. GAS strains 5448 (M1 serotype) and ALAB49 (M53 serotype) also bound hyaluronic acid via M proteins, but hyaluronic acid could increase bacterial adherence independently of M proteins. The identification of host–pathogen mechanisms that affect ECM composition and cell repair responses may facilitate the development of nonantibiotic therapeutics that arrest GAS disease progression in the skin. Bacterial interactions with the extracellular matrix components are important in colonization and infection. Recombinant M proteins of group A Streptococcus (GAS) were shown to bind hyaluronic acid with high affinity via arginine–arginine/serine–arginine (RR/SR) motifs in the conserved C repeat region. Recruitment of hyaluronic acid was shown to delay HaCaT keratinocyte wound healing in an M protein‐specific manner. Our findings suggest a role for glycosaminoglycans as a modulator of GAS infection and potential therapeutic targets.