Sialic acids in infection and their potential use in detection and protection against pathogens - PubMed (original) (raw)
Review
. 2023 Dec 19;5(3):167-188.
doi: 10.1039/d3cb00155e. eCollection 2024 Mar 6.
Sanaz Ahmadipour 1, Peterson de Andrade 1, Alexander N Baker 3, Andrew N Boshra 1 4, Simona Chessa 2, Matthew I Gibson 1 3 5, Pedro J Hernando 2, Irina M Ivanova 2, Jessica E Lloyd 1, María J Marín 6, Alexandra J Munro-Clark 1, Giulia Pergolizzi 2, Sarah-Jane Richards 1 3, Iakovia Ttofi 1 2, Ben A Wagstaff 1, Robert A Field 1 2
Affiliations
- PMID: 38456038
- PMCID: PMC10915975
- DOI: 10.1039/d3cb00155e
Review
Sialic acids in infection and their potential use in detection and protection against pathogens
Simone Dedola et al. RSC Chem Biol. 2023.
Abstract
In structural terms, the sialic acids are a large family of nine carbon sugars based around an alpha-keto acid core. They are widely spread in nature, where they are often found to be involved in molecular recognition processes, including in development, immunology, health and disease. The prominence of sialic acids in infection is a result of their exposure at the non-reducing terminus of glycans in diverse glycolipids and glycoproteins. Herein, we survey representative aspects of sialic acid structure, recognition and exploitation in relation to infectious diseases, their diagnosis and prevention or treatment. Examples covered span influenza virus and Covid-19, Leishmania and Trypanosoma, algal viruses, Campylobacter, Streptococci and Helicobacter, and commensal Ruminococci.
This journal is © The Royal Society of Chemistry.
Conflict of interest statement
Iceni Glycoscience has active programs on the recognition of sialic acids for the development of diagnostics and therapeutics for infectious diseases.
Figures
Fig. 1. Representative sialic acid structural variants. A Symbol Nomenclature for Glycans (SNFG) has been introduced to standardise and simplify glycans drawing. The nonulosonic acids are represented by either a filled diamond shape (NeuAc, KDN etc.) or by a flat diamond shape (Leg, Aci etc.), reported below each of the corresponding chemical structure; a red filled diamond shape is used to indicate a generic sialic acid.
Fig. 2. The mechanism for influenza molecular walker was firstly described by Sakai et al. The HAs on the influenza virus surface bind to the sialic acid on the host cell receptors with the typical carbohydrate–lectin multimeric interaction. The NA hydrolyse the sialic acid, liberating the virus from binding and triggering the “rolling” of the virus on the cell surface. The alternation of HA and NA interaction correspond to an association–disassociation events that generates the crawling and gliding motion of the virus.
Fig. 3. Schematic representation of α-2,6- and α-2,3-Neu5Ac-Gal receptors in humans, pigs, and chicken with structure and SNFG representation (based on De Graaf et al.).
Fig. 4. Human flu virus binds mainly α-2,6-Neu5Ac-Gal, it can infect humans and can be transmitted (top). Avian virus binds mainly α-2,3-Neu5Ac-Gal, it can infect humans if reaches the lower respiratory tract, where the α-2,3-Neu5Ac-Gal is present, however transmission to other individuals is difficult (middle). Avian virus that infects pigs can switch to α-2,6-Neu5Ac-Gal binding, infect humans and potentially cause a pandemic (bottom).
Fig. 5. The Hemagglutinin–Esterase-Fusion surface protein on influenza C virus (left) surface binds to the glycans on host cell surface and the virus is internalised (A), replicated (B) and released (C) outside the cells, facilitated by the esterases action that destroy the binding glycan moiety. The same function is performed by the two different surface proteins HA and NA in influenza A and B viruses (right), D, E and F.
Fig. 6. Tentative chemical structure of the novel sialic acid glycosphingolipid.
Fig. 7. The surface of T. cruzi is covered with mucin containing _O_-linked glycans. The TcTS transfers sialic acid from the host cells surface glycans and serum glycoproteins to the terminal glycan residues of mucin, shielding the parasite from anti α-Gal antibodies. The newly sialylated mucin interacting with Siglec-9 on dendritic cells surface can result in suppressing the release of IL-10. TcTS is released in the blood stream where it alters the glycosylation pattern of surface proteins making the host more susceptible to infections and diseases.
Fig. 8. Schematic representation of Siglecs. Human Siglec receptors contain one N-terminal V-set Ig domain that is responsible for sialic acid binding and several C2-type Ig-like domains acting as spacers and determining the mode of interaction. Siglecs with ITIM (magenta) motifs are inhibitory proteins, whereas Siglecs containing ITAM (purple) motifs are activating receptors, interacting with activation partners DAP10/12. [Figure and caption reproduced from ref. Lenza et al. from open access MDPI, copyright 2020.]
Fig. 9. (A) Schematic representation of human ganglioside structure containing sialic acid residues bound to a ceramide inner core and (B) schematic representation of C. jejuni LOS structures containing sialic acid derivatives that act as structural mimic of the human ganglioside (A), in this case the glycan derivatives are bound to an inner core and lipid A transmembrane tail.
Fig. 10. The interaction of Siglec-7 with C. jejuni strains expressing disialylated LOS may be related to an anti-GQ1b cross-antibody activation, leading to oculomotor weakness in patients with Guilliam-Barré syndrome or the related Miller Fisher syndrome. GQ1b disialylated structures are contained in ganglioside of the human peripheral nervous system.
Fig. 11. (A) Sialic acid core equipped with uncleavable linker; (B) substituent of the sialic acid core; (C) library is printed in the array; (D) binding to the viruses is inhibited in the presence of NA/HA inhibitor; (E) influenza viruses of different strains are assayed against the glycan array; (F) virus of different strains react differently with each glycan generating a signal intensity fingerprint that can be used to characterise the virus/strain.
Fig. 12. Integrated system combining microfluidic, magnetic nanoparticles and RT-PCR. (A) The glyco-nanoparticles are loaded into the microfluidic system; (B) the sample is then loaded in the microfluidic chip; (C) viruses binding to the specific glycan are captured by the magnetic nanoparticles; (D) the unbound material is eluted; (E) the RT-PCR reagents are loaded; (F) the readout provides information of the captured virus(es).
Fig. 13. (I) Nanobiosensor for influenza detection exploiting the trimeric α-2,6-Neu5Ac-galactose ligand (A) conjugated to gold nanoparticles. The presence of the virus generates a colour change in the functionalised colloidal gold solution (B). (II) Gold nanorods functionalised with α-2,3′-Neu5Ac-lactose exploited for the rapid detection of SARS-CoV2.
Fig. 14. Chemical structures of HMO DSLNT and LST-a and LST-c.
Fig. 15. The IT-sialidase of R. gnavus cleaves sialic acid from host cell surface in the gut and rearrange it into 2,7 anhydro sialic acid, providing an advantage over other bacterial species in the gut able to metabolise the standard sialic acid.
Fig. 16. Schematic representation of how sialic acid and its derivatives have been exploited to generate multivalent materials to target receptors Siglecs, selectins and virus proteins to achieve immune modulation, targeted drug delivery and anti-virus treatments [reproduced with permission from Biomaterial Science, Royal Society of Chemistry, copyright 2013].
Fig. 17. Chemical structure of the two NA inhibitors, Oseltamivir and Zanamivir, both mimic the oxacarbenium ion of the sialic acid intermediate formed during the NA action.
Fig. 18. Schematic representation of how Zanamivir bound to a flexible polymer can maximise the interaction with surface NA and increase its binding strength.
Fig. 19. (A) The position of the ligands is elaborated from the 3D structure of the protein; (B) in terms of distance between ligands and orientation; the information is transferred to suitable trimeric structure (C) with scaffold and spacer to achieve the correct orientation and distance to get ligands binding simultaneously.
Fig. 20. β-Cyclodextrin was used as scaffold to immobilise α-2,6′-Neu5Ac-lactose decorated with different linker. The most efficient configuration in terms of therapeutics and prophylactic activity was obtained with a hydrophobic linker. The construct was efficient in both in vitro, ex vivo and in vivo (mice) experiments against human influenza H1N1 infection.
Fig. 21. The binding of CBMs to sialic acid act as a shield, preventing the virus from bind to the same receptors; DAS181, instead, prevents the binding of the virus by cleaving the terminal sialic acid effectively destroying the surface cell receptors.
Fig. 22. The dual Zanamivir-dinitrophenyl conjugate binds to surface NAs of the virus inhibiting the neuraminidase activity and suppressing virus budding from the host cell. The dinitrophenyl (DNP) hapten is highly immunogenic and recruits endogenous anti-DNP antibodies both on the virus-free and the virus-infected cell resulting in their opsonization and the consequent immune-mediated clearance.
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