Spike (S) proteins play a crucial role in penetrating host cells and initiating infection. Without the S protein, viruses would not be able to interact with the cells of potential hosts to cause infection. As a result, the S protein represents an ideal target for antiviral research endeavors.
S proteins cover the surface and bind to the host cell receptor. As compared to the M and E proteins that are primarily involved in virus assembly, the S protein plays a crucial role in penetrating host cells and initiating infection.
Glycan Shields
The spikes are coated with polysaccharide (sugar) molecules to camouflage them, evading surveillance of the host immune system during entry. Another term for this is called “Glycan shields”.
According to research, these sugars are entirely shaping all of our broadly neutralizing antibodies.
In order to enter cells, virus particles and intracellular bacteria use molecules on their surfaces to interact with the cell surface receptors of their target cell which allows them to enter the cell and start their replication cycle.
Neutralizing antibodies can inhibit infectivity by binding to the pathogen and block the molecules needed for cell entry. To elicit their antiviral activity, NAbs bind to the surface epitopes of viral particles to prevent their entry into a host cell.
Based on this information, if we want to control the Spike (S) protein we need to control these sugar molecules on the cell surface receptor in order to elicit protective neutralizing antibodies.
In reality, the surface of a cell is adorned with a forest canopy of sugars, intricate and diverse clusters of carbohydrates that extend like branches and leaves from protein tree trunks.
And, because that canopy is the face that a cell shows to the world, these complex carbohydrates, or glycans, play a critical role in its encounters and interactions with other cells or molecules.
Glycans help to activate, traffic, and regulate immune cells. Certain immune cells are primed to recognize both human and nonhuman sugars so that they can mount a response to the latter or stand down in the presence of the former.
Now, “if you go to an HIV vaccine conference, it’s basically a very high-level glycobiology meeting,” said James Paulson, a molecular biologist at Scripps. “Almost every HIV vaccine person thinks of the sugars first when they’re designing a vaccine”.
That’s primarily because HIV coopts its host’s cellular machinery to blanket itself in human glycans. The surface protein on the virus that allows it to bind to and enter human cells is completely covered by these sugars: At least half of the working protein’s mass is carbohydrate. This so-called glycan shield camouflages the virus as “self” to hide it from the immune system. “It’s like a wolf in sheep’s clothing,” said Philip Gordts, a glycobiologist at the University of California, San Diego.
This phenomenon of immune evasion by molecular mimicry and glycan shielding has been observed and well-characterized across other viral glycoproteins, such as HIV-1 envelope protein (Env), influenza hemagglutinin (HA), and Lassa virus glycoprotein complex (LASV GPC).
The glycans on the spike protein form a glycan shield, which serves as a protective barrier against immune recognition. The glycan shield can hide important epitopes on the spike protein from antibodies, preventing them from binding and neutralizing the virus. The glycan shield also plays a role in modulating the interaction between the spike protein and the ACE2 receptor, which is necessary for viral entry into host cells (Casalino et al., 2020; Zhao et al., 2021).
The glycan shield is composed of a variety of glycans, including high-mannose and complex glycans. The composition and arrangement of these glycans can vary between different coronaviruses and even within the spike protein of the same virus.
While the glycan shield provides a means for the virus to evade the immune system, it is not completely effective. Antibodies that target the spike protein can still be elicited, indicating that some epitopes are accessible despite the presence of the glycan shield (Watanabe et al., 2019).
Understanding the structure and dynamics of the glycan shield is important for the development of therapeutics. By targeting specific glycans or exploiting vulnerabilities in the glycan shield, it may be possible to develop strategies to control viral entry or enhance immune recognition of the virus (Casalino et al., 2020).
Glycan shields and glycoimmunology are two interconnected fields that explore the role of glycans (carbohydrates) in immune responses and disease pathogenesis. Glycoimmunology investigates how glycans interact with glycan-binding proteins called lectins to mediate immune responses (Colomb et al., 2019). The glycan shield refers to the dense layer of glycans that surround viral glycoproteins, such as the spike protein of SARS-CoV-2 (Watanabe et al., 2020). This shield plays a crucial role in evading the host immune system and promoting viral persistence (Watanabe et al., 2020).
Glycans also play a significant role in immune system regulation and inflammation. Alterations in glycosylation have been associated with inflammatory conditions, and specific glycans regulate T-cell activation and immunoglobulin functions (Verhelst et al., 2020). Abnormal antibodies to self-glycans have been observed in COVID-19 patients, which may contribute to autoimmune diseases and neurological disorders (Butler & Gildersleeve, 2020). Furthermore, glycans expressed by parasites, such as Schistosoma, can elicit antibody responses
Glycoimmunology research has also explored the potential of glycosylation in disease diagnosis and treatment. Aberrant IgG glycosylation has been implicated in the pathogenesis of inflammatory bowel disease (IBD) (Miyoshi et al., 2016).
The study of glycan shields and glycoimmunology provides insights into the complex interactions between glycans and the immune system. Understanding these interactions is crucial for developing effective therapeutic interventions.
The Sugar Fix
Specific natural sugar compounds are involved with the proper recognition of foreign S proteins. These sugars form sugar chains on the face of the cell and help identify self from non-self.
The sugar code refers to the role of sugars, specifically glycans, in the immune system. Glycans are complex carbohydrates that are attached to proteins and lipids on the surface of cells. They play a crucial role in various immune processes, including immune cell recognition, signaling, and modulation of immune responses (Varki, 2016).
One aspect of the sugar code is the recognition of glycans by immune cells. Lectins, a type of protein that can bind to specific sugar structures, are involved in this process. Lectins on immune cells can recognize glycans on pathogens, leading to the activation of immune responses against the invading pathogens (Peters & Peters, 2021). Additionally, lectins can also recognize glycans on host cells, allowing immune cells to distinguish between self and non-self (Macauley et al., 2014).
The sugar code also plays a role in the adaptive immune system. The adaptive immune system relies on the recognition of foreign peptide sequences, which are presented to specific T-cell receptors by major histocompatibility receptors (Varki, 2016). However, glycans can also be involved in this process. For example, complex-type N-glycans have been shown to be recognized by HIV antibodies, suggesting that the immune system can respond to both high-mannose and complex-type glycans on viral proteins (Mouquet et al., 2012).
The Manna
One important sugar in the sugar code is mannose, a monosaccharide that is involved in several biological functions.
Mannose-binding lectins, which specifically recognize mannose residues, have been identified in marine algae. These lectins have diverse structural scaffolds and possess common virucidal and anti-cancer properties. For example, red marine algae, a mannose-binding lectin, interacts with complex mannose glycans and exhibits multisite interactions with the glycan, leading to potential therapeutic applications in medicine (Barre et al., 2019).
Overall, mannose plays a significant role in the sugar code and has implications in various biological processes, including infection prevention, cancer therapy, congenital disorders of glycosylation, and bacterial physiology. Further research on mannose and its interactions with other sugars and biological molecules will contribute to a deeper understanding of the sugar code and its implications in health and disease.
Mannose-Binding Lectin
Mannose-binding lectin (MBL) is a crucial component of the innate immune system that plays a significant role in host defense against pathogens (Fujita et al., 2004). MBL is a C-type lectin that recognizes and binds to carbohydrate structures on the surface of microorganisms, including bacteria, viruses, and fungi (Fujita et al., 2004). Upon binding, MBL activates the lectin pathway of the complement system, leading to the opsonization and elimination of pathogens (Fujita et al., 2004).
Several studies have highlighted the importance of MBL in protecting against various infectious diseases. For example, in patients with cystic fibrosis, deficiency in MBL has been associated with increased susceptibility to recurrent lung infections, particularly those caused by Staphylococcus aureus and Pseudomonas aeruginosa (Gabolde et al., 1999). Similarly, MBL has been shown to play a crucial role in innate immunity against opportunistic fungal pathogens, such as Candida albicans and Cryptococcus neoformans (Asbeck et al., 2008).
Furthermore, MBL has been implicated in the pathogenesis of autoimmune diseases. Studies have suggested a relationship between MBL defects and the development of rheumatoid arthritis (Behairy et al., 2022). MBL deficiency has also been associated with an increased risk of developing severe pulmonary disease in patients with cystic fibrosis (Gabolde et al., 1999).
In addition to its role in innate immunity, MBL has been found to have other functions. It has been shown to enhance the clearance of pathogens by phagocytes through its interaction with the mannose receptor (Tsuji et al., 2001).
Overall, MBL is a critical component of the innate immune system that plays a multifaceted role in host defense against pathogens. Its ability to recognize and bind to carbohydrate structures on the surface of microorganisms allows for the activation of the complement system and the elimination of pathogens. However, MBL deficiency or dysfunction can lead to increased susceptibility to infections and the development of autoimmune diseases. Further research is needed to fully understand the mechanisms underlying the role of MBL in host defense and its potential as a therapeutic target.
C-type Lectins
C-type lectins are a diverse family of proteins that play a crucial role in the immune system (Osorio & Sousa, 2011). They are characterized by their ability to bind to carbohydrates in a calcium-dependent manner (Zelensky & Gready, 2005). C-type lectins are involved in various immune processes, including pathogen recognition, immune cell activation, and antigen presentation (Geijtenbeek & Gringhuis, 2009). They act as pattern recognition receptors (PRRs) and can recognize specific carbohydrate structures on pathogens, leading to the activation of immune responses (Geijtenbeek & Gringhuis, 2009).
One important function of C-type lectins is their role in innate immunity. They can recognize and bind to carbohydrates on the surface of pathogens, such as bacteria, fungi, and viruses (Geijtenbeek & Gringhuis, 2009). This recognition triggers downstream signaling events that activate immune cells and initiate immune responses against the invading pathogens (Hoving et al., 2014). For example, C-type lectin receptors (CLRs) have been implicated in antifungal immunity, where they play a crucial role in the recognition and clearance of fungal infections (Hoving et al., 2014).
In addition to their role in pathogen recognition, C-type lectins also play a role in antigen presentation. They can internalize pathogens or pathogen-derived antigens and present them to immune cells, such as dendritic cells, for activation of adaptive immune responses (Geijtenbeek & Gringhuis, 2009). This process is important for the generation of specific immune responses against pathogens and the development of immunological memory.
Furthermore, C-type lectins have been shown to be involved in the regulation of allergic inflammation (Peters & Peters, 2021). While they are generally associated with immune activation, there are cases where pathogens exploit signaling via C-type lectins to suppress the immune response (Peters & Peters, 2021). This highlights the complex and diverse functions of C-type lectins in immune regulation.
Overall, C-type lectins are a diverse family of proteins with important roles in immunity. They are involved in pathogen recognition, immune cell activation, antigen presentation, and immune regulation. Understanding the functions and mechanisms of C-type lectins can provide insights into the development of novel therapeutic strategies for immune-related diseases.
In conclusion, the important thing to understand about Glycoimmunology is that bonded sugar molecules within the body exceed by orders of MAGNITUDE that of RNA, DNA, and proteins COMBINED.
So, naturally these bonded sugar molecules also help dictate the body’s proper immune/inflammatory response against ANYTHING foreign pathogens. Not just viruses, but ANY pathogen!
References:
Glycobiology of immune responses (study)
Glycoimmunology: Ignore at your peril (study)
Other References:
Baboo, S., Diedrich, J., Martínez-Bartolomé, S., X, W., Schiffner, T., Groschel, B., … & Jc, P. (2021). Deglypher: an ultrasensitive method for analysis of viral spike n-glycoforms.. https://doi.org/10.1101/2021.05.13.444041
Jacobs, J. (2020). Neutralizing antibodies mediate virus-immune pathology of covid-19. Medical Hypotheses, 143, 109884. https://doi.org/10.1016/j.mehy.2020.109884
Khan, A., Khan, S., Zia, K., Altowyan, M., Barakat, A., & Ul-Haq, Z. (2022). Deciphering the impact of mutations on the binding efficacy of sars-cov-2 omicron and delta variants with human ace2 receptor. Frontiers in Chemistry, 10. https://doi.org/10.3389/fchem.2022.892093
Marth, J. and Grewal, P. (2008). Mammalian glycosylation in immunity. Nature Reviews Immunology, 8(11), 874-887. https://doi.org/10.1038/nri2417
Ruiz, J., Ramírez, C., & López-Campos, J. (2022). Spike protein of sars-cov-2 omicron variant: an in-silico study evaluating spike interactions and immune evasion. Frontiers in Public Health, 10. https://doi.org/10.3389/fpubh.2022.1052241
Sui, J., Li, W., Murakami, A., Tamin, A., Matthews, L., Wong, S., … & Marasco, W. (2004). Potent neutralization of severe acute respiratory syndrome (sars) coronavirus by a human mab to s1 protein that blocks receptor association. Proceedings of the National Academy of Sciences, 101(8), 2536-2541. https://doi.org/10.1073/pnas.0307140101
Verhelst, X., Dias, A., Colombel, J., Vermeire, S., Vlierberghe, H., Callewaert, N., … & Pinho, S. (2020). Protein glycosylation as a diagnostic and prognostic marker of chronic inflammatory gastrointestinal and liver diseases. Gastroenterology, 158(1), 95-110. https://doi.org/10.1053/j.gastro.2019.08.060
Watanabe, Y., Bowden, T., Wilson, I., & Crispin, M. (2019). Exploitation of glycosylation in enveloped virus pathobiology. Biochimica Et Biophysica Acta (Bba) - General Subjects, 1863(10), 1480-1497. https://doi.org/10.1016/j.bbagen.2019.05.012
Casalino, L., Gaieb, Z., Goldsmith, J., Hjorth, C., Dommer, A., Harbison, A., … & Amaro, R. (2020). Beyond shielding: the roles of glycans in sars-cov-2 spike protein.. https://doi.org/10.1101/2020.06.11.146522
Casalino, L., Gaieb, Z., Goldsmith, J., Hjorth, C., Dommer, A., Harbison, A., … & Amaro, R. (2020). Beyond shielding: the roles of glycans in the sars-cov-2 spike protein. Acs Central Science, 6(10), 1722-1734. https://doi.org/10.1021/acscentsci.0c01056
Shajahan, A., Supekar, N., Gleinich, A., & Azadi, P. (2020). Deducing the n- and o-glycosylation profile of the spike protein of novel coronavirus sars-cov-2. Glycobiology, 30(12), 981-988. https://doi.org/10.1093/glycob/cwaa042
Sztain, T., Ahn, S., Bogetti, A., Casalino, L., Goldsmith, J., Seitz, E., … & Amaro, R. (2021). A glycan gate controls opening of the sars-cov-2 spike protein.. https://doi.org/10.1101/2021.02.15.431212
Watanabe, Y., Berndsen, Z., Raghwani, J., Seabright, G., Allen, J., Pybus, O., … & Crispin, M. (2020). Vulnerabilities in coronavirus glycan shields despite extensive glycosylation. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-16567-0
Watanabe, Y., Bowden, T., Wilson, I., & Crispin, M. (2019). Exploitation of glycosylation in enveloped virus pathobiology. Biochimica Et Biophysica Acta (Bba) - General Subjects, 1863(10), 1480-1497. https://doi.org/10.1016/j.bbagen.2019.05.012
Zhao, X., Chen, H., & Wang, H. (2021). Glycans of sars-cov-2 spike protein in virus infection and antibody production. Frontiers in Molecular Biosciences, 8. https://doi.org/10.3389/fmolb.2021.629873
Butler, D. and Gildersleeve, J. (2020). Abnormal antibodies to self-carbohydrates in sars-cov-2 infected patients.. https://doi.org/10.1101/2020.10.15.341479
Colomb, F., Giron, L., Trbojević-Akmačić, I., Lauc, G., & Abdel-Mohsen, M. (2019). Breaking the glyco-code of hiv persistence and immunopathogenesis. Current Hiv/Aids Reports, 16(2), 151-168. https://doi.org/10.1007/s11904-019-00433-w
Deimel, L., Xue, X., & Sattentau, Q. (2022). Glycans in hiv-1 vaccine design – engaging the shield. Trends in Microbiology, 30(9), 866-881. https://doi.org/10.1016/j.tim.2022.02.004
Diepen, A., Velden, N., Smit, C., Meevissen, M., & Hokke, C. (2012). Parasite glycans and antibody-mediated immune responses inschistosomainfection. Parasitology, 139(9), 1219-1230. https://doi.org/10.1017/s0031182012000273
Miyoshi, E., Shinzaki, S., Fujii, H., Iijima, H., Kamada, Y., & Takehara, T. (2016). Role of aberrant igg glycosylation in the pathogenesis of inflammatory bowel disease. Proteomics - Clinical Applications, 10(4), 384-390. https://doi.org/10.1002/prca.201500089
Verhelst, X., Dias, A., Colombel, J., Vermeire, S., Vlierberghe, H., Callewaert, N., … & Pinho, S. (2020). Protein glycosylation as a diagnostic and prognostic marker of chronic inflammatory gastrointestinal and liver diseases. Gastroenterology, 158(1), 95-110. https://doi.org/10.1053/j.gastro.2019.08.060
Watanabe, Y., Allen, J., Wrapp, D., McLellan, J., & Crispin, M. (2020). Site-specific glycan analysis of the sars-cov-2 spike. Science, 369(6501), 330-333. https://doi.org/10.1126/science.abb9983
Bashiri, S., Koirala, P., Toth, I., & Skwarczynski, M. (2020). Carbohydrate immune adjuvants in subunit vaccines. Pharmaceutics, 12(10), 965. https://doi.org/10.3390/pharmaceutics12100965
Lang, S. and Huang, X. (2020). Carbohydrate conjugates in vaccine developments. Frontiers in Chemistry, 8. https://doi.org/10.3389/fchem.2020.00284
Macauley, M., Crocker, P., & Paulson, J. (2014). Siglec-mediated regulation of immune cell function in disease. Nature Reviews Immunology, 14(10), 653-666. https://doi.org/10.1038/nri3737
Micoli, F., Costantino, P., & Adamo, R. (2018). Potential targets for next generation antimicrobial glycoconjugate vaccines. Fems Microbiology Reviews, 42(3), 388-423. https://doi.org/10.1093/femsre/fuy011
Mouquet, H., Scharf, L., Euler, Z., Liu, Y., Eden, C., Scheid, J., … & Björkman, P. (2012). Complex-type n-glycan recognition by potent broadly neutralizing hiv antibodies. Proceedings of the National Academy of Sciences, 109(47). https://doi.org/10.1073/pnas.1217207109
Peters, K. and Peters, M. (2021). The role of lectin receptors and their ligands in controlling allergic inflammation. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.635411
Varki, A. (2016). Biological roles of glycans. Glycobiology, 27(1), 3-49. https://doi.org/10.1093/glycob/cww086
Ahadova, A., Gebert, J., Doeberitz, M., Kopitz, J., & Kloor, M. (2015). Dose-dependent effect of 2-deoxy-d-glucose on glycoprotein mannosylation in cancer cells. Iubmb Life, 67(3), 218-226. https://doi.org/10.1002/iub.1364
Barre, A., Simplicien, M., Benoist, H., Damme, E., & Rougé, P. (2019). Mannose-specific lectins from marine algae: diverse structural scaffolds associated to common virucidal and anti-cancer properties. Marine Drugs, 17(8), 440. https://doi.org/10.3390/md17080440
Chu, J., Mir, A., Gao, N., Rosa, S., Monson, C., Sharma, V., … & Sadler, K. (2012). A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation. Disease Models & Mechanisms. https://doi.org/10.1242/dmm.010116
Freeze, H. (2009). Towards a therapy for phosphomannomutase 2 deficiency, the defect in cdg-ia patients. Biochimica Et Biophysica Acta (Bba) - Molecular Basis of Disease, 1792(9), 835-840. https://doi.org/10.1016/j.bbadis.2009.01.004
Kong, Q., Liu, Q., Jansen, A., & Curtiss, R. (2010). Regulated delayed expression of rfc enhances the immunogenicity and protective efficacy of a heterologous antigen delivered by live attenuated salmonella enterica vaccines. Vaccine, 28(37), 6094-6103. https://doi.org/10.1016/j.vaccine.2010.06.074
Patyk, E., Jenczak, A., & Katrusiak, A. (2016). Giant strain geared to transformable h-bonded network in compressed β-d-mannose. Physical Chemistry Chemical Physics, 18(16), 11474-11479. https://doi.org/10.1039/c6cp01286h
Asbeck, E., Hoepelman, A., Scharringa, J., Herpers, B., & Verhoef, J. (2008). Mannose binding lectin plays a crucial role in innate immunity against yeast by enhanced complement activation and enhanced uptake of polymorphonuclear cells. BMC Microbiology, 8(1), 229. https://doi.org/10.1186/1471-2180-8-229
Behairy, M., Abdelrahman, A., Abdallah, H., Ibrahim, E., Hashem, H., & Azab, M. (2022). Mannose binding lectin defects and autoimmune diseases. Records of Pharmaceutical and Biomedical Sciences, 6(2), 1-4. https://doi.org/10.21608/rpbs.2022.112972.1121
Fujita, T., Matsushita, M., & Endo, Y. (2004). The lectin-complement pathway - its role in innate immunity and evolution. Immunological Reviews, 198(1), 185-202. https://doi.org/10.1111/j.0105-2896.2004.0123.x
Gabolde, M., Guilloud-Bataille, M., Feingold, J., & Besmond, C. (1999). Association of variant alleles of mannose binding lectin with severity of pulmonary disease in cystic fibrosis: cohort study. BMJ, 319(7218), 1166-1167. https://doi.org/10.1136/bmj.319.7218.1166
Kahlow, B., Nery, R., Skare, T., Ribas, C., Ramos, G., & Petisco, R. (2016). On vascular stenosis, restenosis and mannose binding lectin. Abcd Arquivos
Brasileiros De Cirurgia Digestiva (São Paulo), 29(1), 57-59. https://doi.org/10.1590/0102-6720201600010015
Tsuji, S., Uehori, J., Matsumoto, M., Suzuki, Y., Matsuhisa, A., Toyoshima, K., … & Seya, T. (2001). Human intelectin is a novel soluble lectin that recognizes galactofuranose in carbohydrate chains of bacterial cell wall. Journal of Biological Chemistry, 276(26), 23456-23463. https://doi.org/10.1074/jbc.m103162200
Geijtenbeek, T. and Gringhuis, S. (2009). Signalling through c-type lectin receptors: shaping immune responses. Nature Reviews Immunology, 9(7), 465-479. https://doi.org/10.1038/nri2569
Hoving, J., Wilson, G., & Brown, G. (2014). Signalling c‐type lectin receptors, microbial recognition and immunity. Cellular Microbiology, 16(2), 185-194. https://doi.org/10.1111/cmi.12249
Osorio, F. and Sousa, C. (2011). Myeloid c-type lectin receptors in pathogen recognition and host defense. Immunity, 34(5), 651-664. https://doi.org/10.1016/j.immuni.2011.05.001
Peters, K. and Peters, M. (2021). The role of lectin receptors and their ligands in controlling allergic inflammation. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.635411
Zelensky, A. and Gready, J. (2005). The c-type lectin-like domain superfamily. Febs Journal, 272(24), 6179-6217. https://doi.org/10.1111/j.1742-4658.2005.05031.x
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