Secundino Ismael, Lizcano Anel, Roupé K Markus, Wang Xiaoxia, Cole Jason N, Olson Joshua, Ali S Raza, Dahesh Samira, Amayreh Lenah K, Henningham Anna, Varki Ajit, Nizet Victor
Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA.
Department of Pediatrics, UC San Diego, La Jolla, CA, USA.
J Mol Med (Berl). 2016 Feb;94(2):219-33. doi: 10.1007/s00109-015-1341-8. Epub 2015 Sep 28.
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.
HMW-HA is the first example of a non-sialic acid containing glycan to be recognized by CD33-related Siglecs. HMW-HA engagement of hSiglec-9 attenuates neutrophil activation. Group A Streptococcus exploits hSiglec-9 recognition via its polysaccharide HMW-HA capsule to subvert neutrophil killing.
抑制性CD33相关唾液酸结合凝集素受体（Siglec受体）在与宿主细胞表面聚糖上普遍存在的唾液酸（Sias）结合后，可调节免疫细胞的激活。通过分子模拟，表达唾液酸的病原体B族链球菌结合抑制性人类Siglec-9（hSiglec-9），以抑制中性粒细胞的激活并促进细菌存活。我们意外地发现，hSiglec-9还通过其末端免疫球蛋白样V结构域中与唾液酸结合位点不同的区域，特异性结合另一种普遍存在的宿主聚糖——高分子量透明质酸（HMW-HA）。hSiglec-9对HMW-HA的识别限制了中性粒细胞胞外诱捕网（NET）的形成、氧化爆发和凋亡，将HMW-HA定义为中性粒细胞激活的调节剂。然而，病原体A族链球菌（GAS）表达一种HMW-HA荚膜，该荚膜与hSiglec-9结合，阻断NET的形成和氧化爆发，从而促进细菌存活。因此，单个抑制性凝集素受体可检测两种不同的聚糖“自身相关分子模式”，以维持中性粒细胞的内环境稳定，并且两种主要的人类细菌病原体已经独立进化出分子模拟机制来利用这种免疫调节机制。
HMW-HA是第一个被CD33相关Siglec识别的不含唾液酸的聚糖实例。hSiglec-9与HMW-HA的结合减弱了中性粒细胞的激活。A族链球菌通过其多糖HMW-HA荚膜利用hSiglec-9的识别来颠覆中性粒细胞的杀伤作用。
