Regular physical activity has long been associated with a reduced risk of viral infections, but the mechanisms underlying this protective effect have remained unclear. In this study, Chinese researchers demonstrated how physical exercise enhances the body’s innate antiviral immune response.
The researchers found that physical activity increases hepatic levels of 3-hydroxybutyrate (3-HB), a metabolite that serves as an alternative energy source to glucose. 3-HB is produced during fatty acid oxidation in the liver, and its levels are also elevated during fasting and ketogenic diets.
The study showed that exercise-induced elevation of 3-HB stimulates Gpld1 protein production in the liver. Gpld1 enhances IRF3 activity, promoting the production of type I interferons (IFN-I) and thereby strengthening antiviral immunity.
Physical Exercise Enhances IFN-I Production Through Increased Hepatic Gpld1 Expression
The researchers conducted experiments in mice. Animals were assigned to either a sedentary or an exercise group, with the latter running on exercise wheels three times daily. After one week of exercise, IFN-I levels increased significantly in the blood, liver, and kidneys, whereas a single day of exercise produced no detectable effect.
The liver was identified as the primary source of increased interferon production. Among the proteins upregulated after one week of exercise, only Gpld1 promoted IFN-I production in hepatocytes.
Gpld1 Enhances the IFN-I Response to Viral Infection
Elevated Gpld1 expression increased IFN-I production and the expression of antiviral genes under both basal conditions and during viral infection. Conversely, reduced or absent Gpld1 expression weakened the antiviral immune response.
Gpld1 suppressed the replication of a broad spectrum of viruses, including influenza A virus, herpes simplex virus, vesicular stomatitis virus, and hepatitis B virus. Viral infections were significantly more severe in Gpld1-deficient mice.
Gpld1 Enhances IRF3 Activation
Gpld1 promotes IFN-I production through IRF3. Deletion of Gpld1 reduced interferon expression, whereas the absence of IRF3 completely abolished the effects of Gpld1.
Gpld1 directly interacts with IRF3 and enhances its phosphorylation, a process required for IRF3 activation. Thus, Gpld1 stimulates interferon production by increasing IRF3 activity.
Gpld1 Blocks the Interaction Between PP2A Phosphatase and IRF3
The ability of Gpld1 to enhance antiviral immunity is independent of its enzymatic activity. Even an enzymatically inactive form of Gpld1 retained the ability to stimulate type I interferon production.
Gpld1 competes with the phosphatase PP2A for binding to IRF3. As a result, PP2A cannot efficiently dephosphorylate IRF3, allowing IRF3 to remain active for a longer period.
These findings indicate that Gpld1 enhances IRF3 activation and interferon production by blocking PP2A-mediated inhibition.
Physical Exercise Increases the Levels of the Metabolite 3-HB, Which Promotes Gpld1 Expression
After one week of exercise, several metabolites increased in mice; however, only 3-HB significantly enhanced Gpld1 expression. This effect was concentration-dependent and was observed at both the mRNA and protein levels.
Physical activity increased 3-HB levels in the blood and liver, but not in the lungs. These findings indicate that 3-HB serves as a key metabolic signal linking physical exercise to increased hepatic Gpld1 expression.
3-HB Stimulates IFN-I Production and Enhances Cellular Antiviral Defense
The metabolite 3-HB enhanced antiviral immune responses. In cultured cells, it increased IRF3 activity, stimulated IFN-I production, and enhanced the expression of antiviral genes.
In the presence of 3-HB, cells more effectively suppressed the replication of herpes simplex virus, vesicular stomatitis virus, and hepatitis B virus. However, the protective effects of 3-HB were substantially reduced in the absence of Gpld1.
Thus, 3-HB promotes IRF3 activation, stimulates IFN-I production, and enhances the antiviral activity of type I interferons.
3-HB Increases Hepatic Gpld1 Levels and Enhances the IFN-I Antiviral Response In Vivo
Mouse experiments confirmed the critical role of Gpld1 in antiviral immunity. Gpld1-deficient mice exhibited significantly lower IFN-I levels, and the exercise-induced enhancement of the IFN-I response was markedly reduced or completely absent.
Administration of 3-HB increased Gpld1 expression and IFN-I production, primarily in the liver. Reduced viral loads in tissues and blood accompanied this. However, the protective effect of 3-HB was completely lost in Gpld1-deficient mice.
Furthermore, the absence of Gpld1 reduced survival following infection with herpes simplex virus and vesicular stomatitis virus. These findings confirm that 3-HB promotes Gpld1 expression in vivo and enhances the type I interferon-mediated antiviral response throughout the organism.
Reference
Exercise activates interferon response of the liver via Gpld1 to enhance antiviral innate immunity
