Mechanistic insights into the interaction between gut bacteria polysaccharides and lectins of the host innate immune system

Lamprinaki, Dimitra (2021) Mechanistic insights into the interaction between gut bacteria polysaccharides and lectins of the host innate immune system. Doctoral thesis, University of East Anglia.

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Abstract

Colorectal cancer (CRC) is one of the most common cancer types worldwide, with cases showing the dominance of Bacteroides fragilis and Fusobacterium nucleatum species. While B. fragilis is involved in tumorigenesis through the toxin that it secretes, F. nucleatum is implicated in CRC progression through the recruitment of tumour infiltrating immune cells. However, the mechanisms underpinning the interaction between F. nucleatum ssp. and immune cells remain to be determined. Mammalian lectins expressed by immune or epithelium cells are glycan-binding proteins playing an important role in host cell physiology. The Siglec superfamily and Galectin-3 have been shown to play a role in tumour progression, and Dectin-2 has been shown to activate immune response. Here, we tested the hypothesis that the interaction of cell surface glycoconjugates present on B. fragilis and F. nucleatum ssp. with host lectins may mediate immune response and tumour progression.
Our results showed that, among B. fragilis and the three F. nucleatum subspecies (ATCC 10953, ATCC 25586, ATCC 51191) tested, F. nucleatum ssp. bound to Siglecs and specifically to Siglec-7. Further, we showed that the lipopolysaccharide (LPS) derived from F. nucleatum ssp. bound to Siglec-7 through novel sugar epitopes contained in the LPS structures and we also uncovered a novel LPS structure for F. nucleatum ATCC 51191 strain. Moreover, we purified and characterised the outer membrane vesicles (OMVs) from F. nucleatum ssp. and showed that they interact with Siglec-7, as we demonstrated with the whole bacteria or LPS. We then showed that F. nucleatum ssp. and their derived LPS and OMVs induced a pro-inflammatory phenotype in dendritic cells and a tumour-promoting phenotype in macrophages. Depletion of Siglec-7 in human myeloid cells led to a change in bacteria internalisation and immune response induced by F. nucleatum ssp.
Finally, we showed that F. nucleatum ssp. abundance was elevated in the on-tumour as compared to the off-tumour site across CRC clinical samples tested. In addition, our preliminary data reported the presence of anti-F. nucleatum ssp. IgG antibodies and high levels of the Siglec-7 protein in the serum of CRC patients, which further support F. nucleatum-Siglec-7 interaction as a novel underlying mechanism implicated in CRC.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Jackie Webb
Date Deposited:	21 Oct 2021 15:33
Last Modified:	01 Feb 2023 01:38
URI:	https://ueaeprints.uea.ac.uk/id/eprint/81856
DOI:

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