Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation

Secundino, Ismael, Lizcano, Anel, Roupe, K.Markus, Wang, Xiaoxia, Cole, Jason N., Olson, Joshua, Ali, S.Raza, Dahesh, Samira, Amayreh, Lenah K., Henningham, Anna, Varki, Ajit and Nizet, Victor (2015) Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation. Journal of Molecular Medicine, 94 2: 219-233. doi:10.1007/s00109-015-1341-8

Author Secundino, Ismael
Lizcano, Anel
Roupe, K.Markus
Wang, Xiaoxia
Cole, Jason N.
Olson, Joshua
Ali, S.Raza
Dahesh, Samira
Amayreh, Lenah K.
Henningham, Anna
Varki, Ajit
Nizet, Victor
Title Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation
Journal name Journal of Molecular Medicine   Check publisher's open access policy
ISSN 1432-1440
Publication date 2015-09-28
Year available 2015
Sub-type Article (original research)
DOI 10.1007/s00109-015-1341-8
Open Access Status Not yet assessed
Volume 94
Issue 2
Start page 219
End page 233
Total pages 15
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
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.

Key message
- 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.
Keyword CD33-related Siglecs
Group A Streptococcus (GAS)
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
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Citation counts: TR Web of Science Citation Count  Cited 7 times in Thomson Reuters Web of Science Article | Citations
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