Microbial Hyaluronidases: From Obscure Virulence Factors to Promising Therapeutic Targets

Hyaluronan (HA) is a major extracellular matrix glycosaminoglycan essential for tissue integrity, immune homeostasis, and host defense. Many microbial pathogens exploit host HA by producing hyaluronidases (Hyls), enzymes that degrade HA to promote tissue invasion, nutrient acquisition, immune modulation, and biofilm formation. Unlike mammalian Hyls, microbial Hyls predominantly function as β-elimination lyases, generating unsaturated disaccharides and oligosaccharides with distinct biological activities. Recent mechanistic and structural insights reveal that distinct microbial Hyl variants uniquely shape host–microbe interactions and disease outcomes. This review focuses on microbial Hyls, specifically bacterial Hyls, emphasizing their roles in host immune regulation and inflammatory diseases, particularly in Cutibacterium acnes-mediated acne pathogenesis. We also discuss emerging therapeutic strategies targeting the HA-Hyl axis to modulate inflammation, highlighting their potential as a foundation for novel human therapeutics.