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Sweet Defense: Glucose Fuels Antiviral Immunity

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Genetic diversity among humans determines a wide range of characteristics, from physical appearance to susceptibility to certain diseases, including viral infections. While genetics plays a crucial role in shaping immune responses during viral infections, the impact of non-genetic factors on antiviral defense remains less understood. Researchers at the University of Texas Southwestern identified sugar as a key non-genetic regulator of the antiviral response. Their work sheds light on the roles of both genetic and environmental cues in infection outcomes.

So how is the antiviral response activated in our body?

When mammalian host cells detect foreign substances, such as pathogen-derived nucleic acids (e.g., DNA or RNA), they release signaling molecules called interferons (IFNs). These molecules activate the expression of antiviral genes known as interferon-stimulated genes (ISGs), which help block viral growth. However, achieving homeostasis, the stable state of the body, depends on the proper activation of this response. An under-activated antiviral response leaves the body vulnerable to infections like COVID-19, especially in individuals lacking an ISG called OAS1, which helps fight viruses by detecting and breaking down viral RNAs. In contrast, sustained high levels of ISGs also can lead to excessive inflammation, which can lead to autoimmune diseases like lupus.

Antiviral response varies across individuals and tissues even without infection

Given the importance of a balanced immune response, the research group explored how ISG expression varies across individuals and tissues. They observed significant differences in the expression of a set of ISGs, which are present in all mammals. Specifically, the variation was seen not only between individuals but also across different tissue types, even in the absence of viral infection. These results underscore that antiviral responses are not uniform but are influenced by a combination of genetic diversity and non-genetic factors, like nutrient availability, across individuals and tissues.

To investigate how non-genetic cues affect antiviral responses, the research team decided to focus on the role of mitochondrial metabolism in regulation of antiviral response. They grew human cells in media containing two sugar sources—glucose and galactose— to allow cells to undergo metabolic shift. Glucose triggers glycolysis, a process where cells break down sugar for energy, typically used when energy demands are high. In contrast, galactose shifts metabolism to oxidative phosphorylation (OXPHOS), a process that enhances mitochondrial activity and provides energy more efficiently when oxygen is available. All cells were treated with interferons, and the researchers then compared the expression of antiviral genes between the two sugar conditions to understand how different metabolic environments impact antiviral responses.

Surprisingly, researchers found no changes in the RNA levels of classical ISGs, which are known for their antiviral properties, between the two types of sugar. However, they did observe that the protein levels of some, but not all, pivotal ISGs were altered between the two sugar sources. Specifically, the protein levels of IRF1, an ISG known to inhibit a broad spectrum of DNA viruses, were reduced in cells treated with galactose and a specific type of IFN (IFN-γ), even though its RNA levels remained unchanged. This finding suggests that sugar type can influence the protein expression of certain ISGs via a metabolic shift, despite no changes at the RNA level.

But would changing the sugar source in the media alter the infection outcome?

To answer this question, the researchers tested two unrelated DNA viruses that can infect humans—vaccinia virus and herpes simplex virus-1 (HSV-1). They discovered that glucose enhanced the ability of IFN-γ to block the growth of both viruses. However, this antiviral effect was significantly reduced when cells were grown in galactose. The team identified IRF1, a key protein involved in the antiviral response, as being critical in this process. Under galactose and IFN-γ treatment, IRF1 protein levels dropped, suggesting that glucose is necessary to stabilize IRF1. To confirm that IRF1 is essential for the antiviral response, the researchers deleted the IRF1 gene and found that the vaccinia virus could replicate even in the presence of IFN-γ, regardless of the sugar in the media. This finding further supports that the glucose metabolism can regulate the stability of certain key antiviral proteins, which are essential for blocking viral replication.

Concluding remarks

In summary, while genetic variation contributes to differences in antiviral response, non-genetic factors are equally vital for fine-tuning immune defense and influencing infection outcomes. This study uncovers a new link between glucose metabolism and the regulation of antiviral defense, providing a foundation for developing new treatments for patients with metabolic diseases like diabetes and their comorbidities.

Link to the original post: Chang, T., Alvarez, J., Chappidi, S., Crockett, S., Sorouri, M., Orchard, R. C., & Hancks, D. C. (2024). Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1. PLoS pathogens, 20(10), e1012673. DOI: https://doi.org/10.1371/journal.ppat.1012673

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