Masi, Alessandro Antonio (2025) When Non-Self Looks Like Self: Decoding Lectins–Ligand Recognition across Endogenous and Exogenous Glycans. [Tesi di dottorato]

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Abstract

Glycans are central immune modulators and are principal communicators of the host–microbe interface. Sialylated glycoconjugates such as gangliosides and bacterial lipooligosaccharides (LOS) are some that surface as principal drivers of self/non-self discrimination. Recognition by sialic acid-binding immunoglobulin-like lectins (Siglecs), particularly Siglec-7, is an evolutionary immune checkpoint mechanism hijacked by host and pathogens. This thesis investigates, at the molecular level, structural and functional binding interactions of Siglec-7 with a range of endogenous and exogenous sialoglycans, most notably disialylated gangliosides and bacterial LOS from Neisseria and Fusobacterium species. A multidisciplinary approach including glycan synthesis, structural biology (NMR, mass spectrometry), thermodynamic characterization (ITC, fluorescence titrations), and computational modeling (docking and molecular dynamics) has been employed. Eliciting important findings are the elucidation of conformational requirements vital for Siglec-7 binding, selective recognition of cancer-associated gangliosides such as GD3 and DSGb5, and comprehension of mechanisms of bacterial mimicry via sialylated LOS to escape immune surveillance. Additionally, the study examines the interaction of LOS core epitopes with monoclonal antibody 2C7, offering structural rationale of relevance to vaccine and therapeutic design. In summary, this thesis offers novel molecular insights into immune modulation by glycans and demonstrates the therapeutic potential of inhibiting glyco-immune checkpoints in infectious diseases as well as cancer.

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