Group B Streptococcus Evades Host Immunity by Degrading Hyaluronan

• GBS hyaluronidase degrades pro-inflammatory hyaluronan (HA) fragments to disaccharides
• HA disaccharides block TLR2/4 signaling by both HA fragments and TLR2/4 agonists
• Hyaluronidases secreted by Gram-positive pathogens promote immune evasion
• HA disaccharides and GBS hyaluronidase inhibit inflammation in a lung injury model

SummaryIn response to tissue injury, hyaluronan (HA) polymers are cleaved by host hyaluronidases, generating small fragments that ligate Toll-like receptors (TLRs) to elicit inflammatory responses. Pathogenic bacteria such as group B Streptococcus (GBS) express and secrete hyaluronidases as a mechanism for tissue invasion, but it is not known how this activity relates to immune detection of HA. We found that bacterial hyaluronidases secreted by GBS and other Gram-positive pathogens degrade pro-inflammatory HA fragments to their component disaccharides. In addition, HA disaccharides block TLR2/4 signaling elicited by both host-derived HA fragments and other TLR2/4 ligands, including lipopolysaccharide. Application of GBS hyaluronidase or HA disaccharides reduced pulmonary pathology and pro-inflammatory cytokine levels in an acute lung injury model. We conclude that breakdown of host-generated pro-inflammatory HA fragments to disaccharides allows bacterial pathogens to evade immune detection and could be exploited as a strategy to treat inflammatory diseases.

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