The Glycoscience of Immunity

Zhou, Julie Y.; Oswald, Douglas M.; Oliva, Kelsey D.; Kreisman, Lori S.C.; Cobb, Brian A.

doi:10.1016/j.it.2018.04.004

Cited by 61 publications

(46 citation statements)

References 77 publications

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“…1C). As it is often indicated in immunoregulation (2,7,8), we next confirmed the presence of terminal sialic acid on 293-F Ag85A (expressed via transient transfection) in a dot blot by probing with Sambucus nigra lectin (SNA), a lectin that binds to α2,6-linked sialic acids ( Fig. 1D).…”

Section: Resultssupporting

confidence: 54%

“…This may, in turn, yield undesirable antigens for immune recognition and poor immunogens for eliciting protective immune responses. Moreover, decoration of antigenic protein with host glycans may trigger suppressive immune responses, since host glycans are known for their immunoregulatory properties (2,7,8). The down-regulatory effects of host-associated glycans are also exploited by many pathogens, which display these structures on their surfaces to mimic "self" and thus evade immune recognition (12)(13)(14)(15)(16).…”

Section: Brief Reportmentioning

confidence: 99%

“…We postulated that, when nucleic acid vaccines are used for nonviral pathogens, the proteins expressed by host cells would be structurally and immunogenically different from native pathogen protein, due to the elaboration of host posttranslational modifications (PTMs), especially glycosylation for targets that enter the secretory pathway. Glycans may hinder or alter important epitopes and/or down-regulate immune responses through many regulatory immune cell receptors (2). Therefore, the glycans on the proteins expressed through nucleic acid vaccines may undesirably influence the immune responses against the antigen.…”

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confidence: 99%

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Host protein glycosylation in nucleic acid vaccines as a potential hurdle in vaccine design for nonviral pathogens

Ozdilek

Paschall

Dookwah

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Nucleic acid vaccines introduce the genetic materials encoding antigenic proteins into host cells. If these proteins are directed into the secretory pathway with a signal/leader sequence, they will be exposed to the host’s glycosylation machinery, and, if their amino acid sequences contain consensus sequons for N-linked glycosylation, they may become glycosylated. The presence of host glycans on the proteins of microbial origin may prevent a strong protective immune response either through hindering access to key epitopes by lymphocytes or through altering immune responses by binding to immunoregulatory glycan-binding receptors on immune cells. Ag85A expressed by Mycobacterium tuberculosis (Mtb) is a bacterial surface protein that is commonly used in nucleic acid vaccines in multiple clinical trials. Here we show that, when Ag85A is expressed in mammalian cells, it is glycosylated, does not induce a strong humoral immune response in mice, and does not activate Ag85A-specific lymphocytes as highly as Ag85A natively expressed by the bacterium. Our study indicates that host glycosylation of the vaccine target can impede its antigenicity and immunogenicity. Glycosylation of the antigenic protein targets therefore must be carefully evaluated in designing nucleic acid vaccines.

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Section: Resultssupporting

confidence: 54%

Section: Brief Reportmentioning

confidence: 99%

mentioning

confidence: 99%

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Host protein glycosylation in nucleic acid vaccines as a potential hurdle in vaccine design for nonviral pathogens

Ozdilek

Paschall

Dookwah

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent reviews highlight the importance of protein-glycan interactions in immunity (Marth and Grewal, 2008;Van Kooyk and Rabinovich, 2008;Zhou et al, 2018). In this review, we highlight key examples of how N-glycosylation of membrane immune receptors influences receptor properties, such as lateral interactions with neighboring molecules, clustering and diffusion behavior, all modulating receptor function (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Biological and Technical Challenges in Unraveling the Role of N-Glycans in Immune Receptor Regulation

et al. 2020

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N-glycosylation of membrane receptors is important for a wide variety of cellular processes. In the immune system, loss or alteration of receptor glycosylation can affect pathogen recognition, cell-cell interaction, and activation as well as migration. This is not only due to aberrant folding of the receptor, but also to altered lateral mobility or aggregation capacity. Despite increasing evidence of their biological relevance, glycosylation-dependent mechanisms of receptor regulation are hard to dissect at the molecular level. This is due to the intrinsic complexity of the glycosylation process and high diversity of glycan structures combined with the technical limitations of the current experimental tools. It is still challenging to precisely determine the localization and site-occupancy of glycosylation sites, glycan micro-and macro-heterogeneity at the individual receptor level as well as the biological function and specific interactome of receptor glycoforms. In addition, the tools available to manipulate N-glycans of a specific receptor are limited. Significant progress has however been made thanks to innovative approaches such as glycoproteomics, metabolic engineering, or chemoenzymatic labeling. By discussing examples of immune receptors involved in pathogen recognition, migration, antigen presentation, and cell signaling, this Mini Review will focus on the biological importance of N-glycosylation for receptor functions and highlight the technical challenges for examination and manipulation of receptor N-glycans.

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“…Glycans play a major role in the regulation of immune cell functions [17]. The glycome of the CNS is unique in that it is predominantly composed of glycolipids -as opposed to glycoproteins in peripheral systems [18] -with gangliosides being the most abundant species [19].…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory role of GM1 and modulatory effects of gangliosides on microglia functions

Galleguillos

Qian

Steinberg

et al. 2020

Preprint

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Gangliosides are sialic acid-containing glycosphingolipids highly enriched in the brain. Located mainly at the plasma membrane, gangliosides play important roles in signaling and cell-to-cell communication. Lack of gangliosides causes severe early onset neurodegenerative disorders, while more subtle deficits have been reported in Parkinson's disease and in Huntington's disease, two misfolded protein diseases with a neuroinflammatory component. On the other hand, administration of ganglioside GM1 provides neuroprotection in both diseases and in several other models of neuronal insult. While most studies have focused on the role of endogenous gangliosides and the effects of exogenously administered GM1 in neurons, their contribution to microglia functions that are affected in neurodegenerative conditions is largely unexplored.Microglia are the immune cells of the brain and play important homeostatic functions in health and disease. In this study, we show that administration of exogenous GM1 exerts a potent antiinflammatory effect on microglia activated with LPS, IL-1β or upon phagocytosis of latex beads.These effects are partially reproduced by L-t-PDMP, a compound that stimulates the activity of the ganglioside biosynthetic pathway, while inhibition of ganglioside synthesis with GENZ-123346 increases microglial transcriptional response to LPS. We further show that administration of GM1 increases the uptake of apoptotic bodies and latex beads by microglia, as well as microglia migration and chemotaxis in response to ATP. On the contrary, decreasing microglial ganglioside levels results in a partial impairment in both microglial activities. Finally, increasing cellular ganglioside levels results in decreased expression and secretion of microglial brain derived neurotrophic factor (BDNF). Altogether, our data suggest that gangliosides are important modulators of microglia functions that are crucial to healthy brain homeostasis, and reveal that administration of ganglioside GM1 exerts an important anti-inflammatory activity that could be exploited therapeutically.

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The Glycoscience of Immunity

Cited by 61 publications

References 77 publications

Host protein glycosylation in nucleic acid vaccines as a potential hurdle in vaccine design for nonviral pathogens

Host protein glycosylation in nucleic acid vaccines as a potential hurdle in vaccine design for nonviral pathogens

Biological and Technical Challenges in Unraveling the Role of N-Glycans in Immune Receptor Regulation

Anti-inflammatory role of GM1 and modulatory effects of gangliosides on microglia functions

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