Group B Streptococcus Evades Host Immunity by Degrading Hyaluronan

In 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. [Display omitted] •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 During tissue injury, host hyaluronidases cleave high molecular-weight hyaluronan (HA) into pro-inflammatory fragments that activate TLR2 or TLR4. Kolar et al. demonstrate that bacterial hyaluronidases, secreted by certain Gram-positive pathogens, cleave intact or fragmented HA into disaccharides that are themselves non-stimulatory and block binding of stimulatory HA fragments.