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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).

Conflict of Interest

The authors declare that they have no competing interests.

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    Authors and Affiliations

    1. Glycobiology Research and Training Center, UC San Diego, La Jolla, CA, USA

      Ismael Secundino, Anel Lizcano, K. Markus Roupé, Xiaoxia Wang, S. Raza Ali, Anna Henningham, Ajit Varki & Victor Nizet

    2. Department of Pediatrics, UC San Diego, La Jolla, CA, USA

      Ismael Secundino, K. Markus Roupé, Jason N. Cole, Joshua Olson, S. Raza Ali, Samira Dahesh, Lenah K. Amayreh, Anna Henningham & Victor Nizet

    3. Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, Mexico

      Ismael Secundino

    4. Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA

      Anel Lizcano, Xiaoxia Wang & Ajit Varki

    5. Faculty of Medicine, Lund University, Lund, Sweden

      K. Markus Roupé

    6. Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Queensland, Australia

      Jason N. Cole

    7. Department of Medicine, UC San Diego, La Jolla, CA, USA

      Ajit Varki

    8. Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA, USA

      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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