Siglec-7 mediates immunomodulation by colorectal cancer-associated Fusobacterium nucleatum ssp. animalis

Lamprinaki, Dimitra, Garcia-Vello, Pilar, Marchetti, Roberta, Hellmich, Charlotte, McCord, Kelli A., Bowles, Kristian M., Macauley, Matthew S., Silipo, Alba, De Castro, Cristina, Crocker, Paul R. and Juge, Nathalie (2021) Siglec-7 mediates immunomodulation by colorectal cancer-associated Fusobacterium nucleatum ssp. animalis. Frontiers in Immunology, 12. ISSN 1664-3224

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Abstract

Fusobacterium nucleatum is involved in the development of colorectal cancer (CRC) through innate immune cell modulation. However, the receptors of the interaction between F. nucleatum ssp. and immune cells remain largely undetermined. Here, we showed that F. nucleatum ssp. animalis interacts with Siglecs (sialic acid–binding immunoglobulin-like lectins) expressed on innate immune cells with highest binding to Siglec-7. Binding to Siglec-7 was also observed using F. nucleatum-derived outer membrane vesicles (OMVs) and lipopolysaccharide (LPS). F. nucleatum and its derived OMVs or LPS induced a pro-inflammatory profile in human monocyte-derived dendritic cells (moDCs) and a tumour associated profile in human monocyte-derived macrophages (moMϕs). Siglec-7 silencing in moDCs or CRISPR-cas9 Siglec-7-depletion of U-937 macrophage cells altered F. nucleatum induced cytokine but not marker expression. The molecular interaction between Siglec-7 and the LPS O-antigen purified from F. nucleatum ssp. animalis was further characterised by saturation transfer difference (STD) NMR spectroscopy, revealing novel ligands for Siglec-7. Together, these data support a new role for Siglec-7 in mediating immune modulation by F. nucleatum strains and their OMVs through recognition of LPS on the bacterial cell surface. This opens a new dimension in our understanding of how F. nucleatum promotes CRC progression through the generation of a pro-inflammatory environment and provides a molecular lead for the development of novel cancer therapeutic approaches targeting F. nucleatum-Siglec-7 interaction.

Item Type: Article
Additional Information: Funding Information: The authors gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); this research was funded by the BBSRC Institute Strategic Programme Gut Microbes and Health BB/R012490/1 Funding Information: The authors gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); this research was funded by the BBSRC Institute Strategic Programme Gut Microbes and Health BB/R012490/1 and its constituent project BBS/E/F/000PR10353 (Theme 1, Determinants of microbe-host responses in the gut across life). DL was supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership grant number BB/M011216/1. PGV acknowledges financial support from the European Commission via the International Training Network Train2Target (721484). AS was supported by PRIN 2017 (2017XZ2ZBK, 2019-2022), RM was supported by the European Research Council (ERC) under the European Union?s Horizon 2020 research and innovation programme, grant agreement number 851356. Work in the PRC lab was supported by Wellcome Trust grant 103744/Z/14/Z. MM acknowledges funding from GlycoNet, NSERC, and a Canada Tier II research chair in Chemical Glycoimmunology. KM acknowledges support through an Alberta Graduate Excellence Scholarship. Publisher Copyright: © Copyright © 2021 Lamprinaki, Garcia-Vello, Marchetti, Hellmich, McCord, Bowles, Macauley, Silipo, De Castro, Crocker and Juge.
Uncontrolled Keywords: colorectal cancer,fusobacterium nucleatum,innate immunity,lipopolysaccharide,outer membrane vesicle,siglec-7,immunology and allergy,immunology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2723
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 29 Oct 2021 00:41
Last Modified: 25 Nov 2021 01:40
URI: https://ueaeprints.uea.ac.uk/id/eprint/81924
DOI: 10.3389/fimmu.2021.744184

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