期刊
JOURNAL OF MOLECULAR MEDICINE-JMM
卷 94, 期 2, 页码 219-233出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00109-015-1341-8
关键词
CD33-related Siglecs; Hyaluronan; Neutrophils; Group A Streptococcus (GAS)
资金
- NIH/NHLBI Programs of Excellence in Glycosciences [P01-HL107150]
- NIH/NIAID [R01-AI077780]
- UC MEXUS-CONACYT Postdoctoral Research Fellowship
- UCSD/SDSU NIH/IRACDA Postdoctoral Fellowship Program [K12 GM068524]
- Wenner-Gren Foundations Fellowship, Sweden
Inhibitory CD33-related Siglec receptors regulate immune cell activation upon engaging ubiquitous sialic acids (Sias) on host cell surface glycans. Through molecular mimicry, Sia-expressing pathogen group B Streptococcus binds inhibitory human Siglec-9 (hSiglec-9) to blunt neutrophil activation and promote bacterial survival. We unexpectedly discovered that hSiglec-9 also specifically binds high molecular weight hyaluronan (HMW-HA), another ubiquitous host glycan, through a region of its terminal Ig-like V-set domain distinct from the Sia-binding site. HMW-HA recognition by hSiglec-9 limited neutrophil extracellular trap (NET) formation, oxidative burst, and apoptosis, defining HMW-HA as a regulator of neutrophil activation. However, the pathogen group A Streptococcus (GAS) expresses a HMW-HA capsule that engages hSiglec-9, blocking NET formation and oxidative burst, thereby promoting bacterial survival. Thus, a single inhibitory lectin receptor detects two distinct glycan self-associated molecular patterns to maintain neutrophil homeostasis, and two leading human bacterial pathogens have independently evolved molecular mimicry to exploit this immunoregulatory mechanism.
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