Molecular Basis of Siglec-7 Recognition by <i>Neisseria meningitidis</i> Serogroup Y CPS: Implications for Immune Evasion

Siglecs, sialic-acid-binding immunoglobulin-like lectins, are key immune cell receptors that recognize sialic acid residues on cell surfaces. Pathogens and tumor cells exploit Siglecs to evade immune responses and modulate immunity, contributing significantly to infectious disease and cancer pathogenesis. Siglec-7, primarily expressed on natural killer (NK) cells, functions as an inhibitory receptor, tightly regulating the immune activity. This study investigates the interaction between Siglec-7 and the capsular polysaccharide (CPS) of Neisseria meningitidis serogroup Y (Men-Y), a bacterium whose sialylated CPS is critical for virulence. We demonstrate that Men-Y CPS binds to inhibitory Siglec-7, potentially dampening immune recognition. We employed a multifaceted approach, combining biochemical and biophysical techniques to dissect this interaction. Enzyme-linked immunosorbent assays (ELISAs) and fluorescence titrations quantified the binding specificity and affinity. Ligand- and protein-based nuclear magnetic resonance (NMR) spectroscopy, coupled with computational modeling, provides detailed molecular insights. We highlight the critical influence of the Men-Y CPS conformation and sialic acid presentation on Siglec-7 binding. The specific arrangement of α-2,6-linked sialic acids on the CPS is crucial for Siglec-7 binding, demonstrating the importance of the CPS 3D structure. Preliminary immunological assays using stimulated U937 cells (a promonocytic cell line) further support the immunomodulatory role of Siglec-7 mediated by Men-Y CPS. These results offer valuable insights into the development of targeted therapeutic strategies against bacterial infections.

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Journal
JACS Au
Published
2025-04-30
DOI
https://doi.org/10.1021/jacsau.5c00214
Citations
4
Primary Topic
Bacterial Infections and Vaccines
Type
article
Field-Weighted Citation Impact
4.73

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Molecular Basis of Siglec-7 Recognition by Neisseria meningitidis Serogroup Y CPS: Implications for Immune Evasion

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Molecular Basis of Siglec-7 Recognition by Neisseria meningitidis Serogroup Y CPS: Implications for Immune Evasion

Yvette van Kooyk, Celeste Abreu, Darielys Santana-Mederos, Paola Salvatore, Cristina Di Carluccio, Antonio Molinaro, F. Albano, María Pia Lenza, Ondřej Vaněk, Ferran Nieto‐Fabregat, A. Masi, Marco Fragai, Alba Silipo, Vito Longo, Yury Valdés-Balbín, Vicente Vérez-Bencomo, Roberta Marchetti, Fabrizio Chiodo, Geppino Falco, Tania Gerpe Amor
article en
4 citations

Abstract

Siglecs, sialic-acid-binding immunoglobulin-like lectins, are key immune cell receptors that recognize sialic acid residues on cell surfaces. Pathogens and tumor cells exploit Siglecs to evade immune responses and modulate immunity, contributing significantly to infectious disease and cancer pathogenesis. Siglec-7, primarily expressed on natural killer (NK) cells, functions as an inhibitory receptor, tightly regulating the immune activity. This study investigates the interaction between Siglec-7 and the capsular polysaccharide (CPS) of Neisseria meningitidis serogroup Y (Men-Y), a bacterium whose sialylated CPS is critical for virulence. We demonstrate that Men-Y CPS binds to inhibitory Siglec-7, potentially dampening immune recognition. We employed a multifaceted approach, combining biochemical and biophysical techniques to dissect this interaction. Enzyme-linked immunosorbent assays (ELISAs) and fluorescence titrations quantified the binding specificity and affinity. Ligand- and protein-based nuclear magnetic resonance (NMR) spectroscopy, coupled with computational modeling, provides detailed molecular insights. We highlight the critical influence of the Men-Y CPS conformation and sialic acid presentation on Siglec-7 binding. The specific arrangement of α-2,6-linked sialic acids on the CPS is crucial for Siglec-7 binding, demonstrating the importance of the CPS 3D structure. Preliminary immunological assays using stimulated U937 cells (a promonocytic cell line) further support the immunomodulatory role of Siglec-7 mediated by Men-Y CPS. These results offer valuable insights into the development of targeted therapeutic strategies against bacterial infections.

JACS AuVol. 5(5)
Charles University (CZ), Finlay Institute (CU), Interuniversity Consortium for Magnetic Resonance (IT), Amsterdam University Medical Centers (NL), National Research Council (IT), University of Florence (IT), University of Naples Federico II (IT), Vrije Universiteit Amsterdam (NL)
Ministerstvo Školství, Mládeže a Tělovýchovy, Grantová Agentura České Republiky, Accademia Nazionale dei Lincei, Ministero dell'Università e della Ricerca, H2020 European Research Council, H2020 Marie Skłodowska-Curie Actions
Zero hunger
Openalex Percentile: Top 5%
Bacterial Infections and Vaccines
4.73
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