Alongside SARS-CoV-2, six other HCoVs have been identified, ranging from causing mild symptoms of the common cold to severe pathologies.
With the continuous emergence of new HCoVs in the human population, there is an urgent need to develop effective antiviral therapies that can target a broad range of HCoVs, including SARS-CoV-2 and its emerging variants.
The Structure and Response of SARS-CoV-2
SARS-CoV-2 is an enveloped RNA virus with a positive-sense, single-stranded genome. It induces an interferon (IFN) response in host cells. This antiviral response is primarily mediated by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and the mitochondrial antiviral signaling protein (MAVS) pathway.
Upon activation, MAVS recruits TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 translocates into the nucleus, leading to the expression of type I interferons (IFN-I) that drive the expression of IFN-stimulated genes (ISGs) to control SARS-CoV-2 infection. The responsiveness to IFN-I is crucial in determining the severity of SARS-CoV-2 infection.
The Role of O-GlcNAcylation in IFN Signaling
In Vitro and In Vivo Studies
In a study, researchers established SARS-CoV-2 infection models using human lung epithelial cells (Calu-3) and human liver cancer cells (Huh7). They treated the cells with GlcN and observed a significant reduction in SARS-CoV-2 replication, as measured by the expression of the viral spike protein and viral titers in the cell culture supernatant. GlcN inhibited SARS-CoV-2 infection with an EC50 value of 11.82 mM, without causing measurable cytotoxicity.
To evaluate the antiviral effect of GlcN in vivo, the researchers assessed its safety and efficacy in a mouse model of SARS-CoV-2 infection. Oral administration of GlcN significantly reduced viral loads in the lungs and tracheas of infected mice, leading to a decrease in lung inflammation. The results demonstrated that GlcN restricts SARS-CoV-2 replication and alleviates virus-induced lung injury in vivo.
Broad-Spectrum Antiviral Activity Against Other HCoVs
In addition to its effectiveness against SARS-CoV-2, GlcN also showed potent antiviral activity against other HCoVs, including HCoV-229E (229E) and HCoV-OC43 (OC43). GlcN inhibited the replication of 229E and OC43 in human lung epithelial cells,
demonstrating its broad-spectrum antiviral potential against different HCoVs. The inhibition of multiple HCoVs suggests that GlcN could be an effective therapeutic strategy against a range of coronaviruses, including those with pandemic potential.
Mechanism of Action
The exact mechanism by which GlcN exerts its antiviral activity is still under investigation. It is proposed that GlcN enhances MAVS O-GlcNAcylation, leading to the activation of downstream signaling pathways involved in IFN production and antiviral defense. O-GlcNAcylation of MAVS promotes its aggregation and interaction with TBK1, facilitating IFN signaling. This enhanced IFN response helps control viral replication and limit the spread of infection..
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O-GlcNAcylation has been implicated in various cellular processes, such as transcription, signaling, metabolism, and stress response. Recently, O-GlcNAcylation has also emerged as a key regulator of innate immunity and antiviral defense. Several studies have shown that O-GlcNAcylation modulates the activation and function of key components of the interferon (IFN) signaling pathway, such as mitochondrial antiviral signaling protein (MAVS), retinoic acid-inducible gene I (RIG-I), and IFN regulatory factors (IRFs) [2].
MAVS is a mitochondrial adaptor protein that mediates the downstream signaling of RIG-I-like receptors (RLRs), which are cytosolic sensors of viral RNA. Upon viral infection, RLRs recognize viral RNA and undergo conformational changes that expose their caspase activation and recruitment domains (CARDs).
These CARDs interact with the CARD domain of MAVS, leading to the formation of MAVS aggregates on the mitochondrial membrane. These aggregates recruit and activate various kinases and ubiquitin ligases, such as TBK1, IKKε, TRAF2, TRAF3, and TRAF6, which in turn phosphorylate and activate IRFs and NF-κB. These transcription factors then translocate to the nucleus and induce the expression of type I IFNs (IFN-α and IFN-β) and other proinflammatory cytokines [3].
O-GlcNAcylation has been shown to be essential for MAVS activation and IFN signaling. In a seminal study by Liu et al., it was demonstrated that MAVS is O-GlcNAcylated at multiple sites upon viral infection or poly(I:C) stimulation. This O-GlcNAcylation is mediated by OGT and is dependent on the HBP flux. O-GlcNAcylation stabilizes MAVS aggregates and enhances its interaction with TBK1 and IKKε. Conversely, inhibition of OGT or OGA reduces MAVS O-GlcNAcylation and impairs MAVS-mediated IFN signaling. Moreover, mice with reduced HBP flux or OGT activity are more susceptible to viral infection and show impaired IFN production [4].
Interestingly, glucosamine (GlcN), a commonly used dietary supplement for osteoarthritis, has been found to increase MAVS O-GlcNAcylation and enhance MAVS-mediated IFN signaling. GlcN is an amino sugar that can enter the HBP and increase the intracellular levels of UDP-GlcNAc, the donor substrate for OGT.
GlcN treatment augments MAVS O-GlcNAcylation and promotes its aggregation and interaction with TBK1 and IKKε in response to viral infection or poly(I:C) stimulation. GlcN also increases the expression of type I IFNs and other proinflammatory cytokines in vitro and in vivo.
Furthermore, GlcN confers broad-spectrum antiviral activity against various RNA viruses, such as influenza A virus (IAV), vesicular stomatitis virus (VSV), encephalomyocarditis virus (EMCV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). GlcN protects mice from lethal IAV infection by enhancing IFN production and reducing viral load in the lungs. GlcN also inhibits SARS-CoV-2 replication in human lung epithelial cells by inducing IFN pathways [5].
In summary, O-GlcNAcylation is a crucial posttranslational modification that regulates MAVS activation and IFN signaling. GlcN, a dietary supplement that boosts HBP flux and O-GlcNAcylation, has potent antiviral effects against various RNA viruses by enhancing host innate immunity. These findings suggest that modulating O-GlcNAcylation may be a promising strategy for developing novel antiviral therapeutics.
References:
[1] Hart GW et al., Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem. 2011;80:825-58.
[2] Ma Z et al., O-GlcNAcylation in immunity and inflammation: an intricate system (review). Int J Mol Med. 2018;42(3):1139-1148.
[3] Kawai T and Akira S, The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373-84.
[4] Liu Q et al., O-GlcNAc transferase promotes influenza A virus-induced cytokine storm by targeting interferon regulatory factor-5. Sci Adv. 2020;6(11):eaaz7086.
[5] Liu Q et al., Glucosamine promotes MAVS-mediated type I interferon production during viral infection. Cell Rep. 2020;33(1):108227.
Clinical Implications
GlcN is an FDA-approved dietary supplement widely available over-the-counter. Its safety profile has been established, with common side effects being mild gastrointestinal symptoms. Considering its potential antiviral activity against HCoVs, including SARS-CoV-2, GlcN could be repurposed as a therapeutic agent for the treatment of COVID-19 and other coronavirus infections. Further clinical studies are necessary to determine the optimal dosage, treatment duration, and efficacy of GlcN in COVID-19 patients.
Conclusion
Glucosamine, a dietary supplement commonly used for joint health, has shown promising broad-spectrum antiviral activity against human coronaviruses, including SARS-CoV-2. By enhancing MAVS O-GlcNAcylation and promoting IFN signaling, GlcN exhibits potent antiviral effects in vitro and in vivo. Its ability to inhibit multiple HCoVs suggests its potential as a therapeutic option against current and future coronavirus outbreaks. However, further research is needed to fully understand the underlying mechanisms and optimize its clinical application.
reference link :https://www.nature.com/articles/s41392-023-01483-8
