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

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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.

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Acknowledgments

Major research funding was provided by the NIH/NHLBI Programs of Excellence in Glycosciences Grant P01-HL107150 (AV and VN) and by NIH/NIAID grant R01-AI077780 (VN), a UC MEXUS-CONACYT Postdoctoral Research Fellowship (IS), the UCSD/SDSU IRACDA Postdoctoral Fellowship Program (AL), and a Wenner-Gren Foundations Fellowship, Sweden (KMR).

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The authors declare that they have no competing interests.

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Correspondence to Victor Nizet.

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Anel Lizcano, K. Markus Roupé, Xiaoxia Wang and Jason N. Cole contributed equally to this work.

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Secundino, I., Lizcano, A., Roupé, K.M. et al. Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation. J Mol Med 94, 219–233 (2016). https://doi.org/10.1007/s00109-015-1341-8

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  • DOI: https://doi.org/10.1007/s00109-015-1341-8

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