Cell protection, immunomodulation and inhibition of viruses by endogenous substances
by Jan Grabowski, TWINCORE – Zentrum für Experimentelle und Klinische Infektionsforschung
The isomeric structure of itaconic acid. Credit: CC-BY F. Chen et al.
The endogenous itaconic acid molecule has antiviral and anti-inflammatory effects, as recently demonstrated by researchers from TWINCORE. In collaboration with scientists from the Helmholtz Center for Infection Research in Braunschweig and the Helmholtz Saarland Pharmaceutical Research Institute, they have now investigated the closely related substance citric acid. The result: Citraconic acid protects cells through its antioxidant and anti-inflammatory properties. It also inhibits the release of flu viruses from human cells. They published these results in the journal Natural Metabolism.
“Itaconic acid has two isomers, natural relatives that differ only slightly in their chemical structure, mesaconic acid and citraconic,” said PD Dr. Frank Pessler, head of the “Biomarkers for Infectious Diseases” working group at the Institute for Experimental Infection Research at TWINCORE, Center for Experimental and Clinical Infection Research in Hannover. All three substances occur naturally in higher organisms, and Pessler’s research group first detected them in the lymph nodes and spleen, an important organ of the immune system, in 2021. They are the most promising for drug development,” explains Pessler.
Researchers found that citraconic acid had several positive effects on the immune system at once. “We found that citraconic acid activates an important signaling pathway in the immune system,” Pessler said. “The so-called NRF2 pathway controls anti-oxidative and anti-inflammatory processes that can protect cells from harmful influences.” The effect of citric acid here is many times stronger than that of itaconic and mesaconic acids.
When the researchers infected human cells with the flu virus and simultaneously treated them with citraconic acid, they observed strong inhibition of a messenger substance that triggers inflammation. “This inhibits the interferon type 1 signaling cascade, thereby reducing proinflammatory cytokines and chemokines,” Pessler said. “These are signaling molecules that initiate and amplify processes in the immune system.”
In the same experiment, the researchers also tested the effects of the three isomers on flu virus replication. They found that citraconic acid in particular almost completely suppressed the release of viral particles from infected cells. Citraconic acid is also stronger than itaconic and mesaconic acids in this area. Through this simultaneous inhibition of viral replication, messenger substances, and oxidizing molecules that damage cells, Pessler hopes that citric acid-based drugs will help patients with severe viral infections such as influenza, but also COVID-19. Such inhibitors may find clinically important applications.
Pessler and his team also found that itaconic acid and citric acid interact directly. Here, the mitochondrial enzyme ACOD1 plays a central role. ACOD1 mediates itaconic acid synthesis in inflamed tissues.
“Citraconic acid prevents the production of itaconic acid by binding directly to the active site of the enzyme. Such an inhibitor was previously unknown,” said Dr. Fang Fang Chen. The biotechnologist does most of the experimental work as part of his doctoral thesis. “Too much itaconic acid can weaken the immune system. Therefore, administration of citric acid can lead to improved immune system performance. This can help with advanced sepsis, or blood poisoning, or in people whose immune system does not respond well to vaccinations. ,” he noted.
“Other research groups have shown that itaconic acid can promote the growth of certain tumors,” Pessler said. Again, citric acid can prevent the formation of itaconic acid. Pessler observed, “ACOD1 inhibitors based on citraconic acid could therefore constitute a new class of anti-cancer drugs.”
“We have filed a patent for a medical application of citraconic acid,” concludes Pessler. “However, we still have a lot of work ahead of us before we know if and how drugs based on citric acid can be used properly.”
Itaconic acid synthesis reduces interferon response and inflammation in influenza A . virus infection
F. Chen et al, Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon response and oxidative stress, and modulates inflammation and cellular metabolism, Natural Metabolism (2022). DOI: 10.1038/s42255-022-00577-x
Provided by TWINCORE – Zentrum für Experimentelle und Klinische Infektionsforschung
Quote: Cell protection, immunomodulation, and viral inhibition by endogenous substances (2022, 7 July) retrieved 7 July 2022 from https://phys.org/news/2022-07-cell-immunomodulation-virus-inhibition-endogenous.html
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