Scientists have found that many people who die from the new coronavirus seem to be more damaged by their own immune systems than by the virus itself. Virus infection sparks a “cytokine storm”, a surge in cell signaling proteins. This can cause inflammation, damage to the lungs and body tissues, and can lead to organ failure and death.
But this phenomenon is not unique to patients with new coronary pneumonia, and sometimes in patients with severe influenza. A new study has revealed the metabolic mechanisms that cause this inflammatory to spiral out of control.
Viral infection sits on glucose metabolism
In a paper published in the journal Science Advances, researchers say that when live mice and human cells become infected with influenza A virus, they trigger a series of cellular activity that opens up a path of glucose metabolism. These changes, in turn, lead to the production of large numbers of cytokines, so blocking a key enzyme in glucose metabolism has the potential to prevent a deadly cytokine surge.
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While the focus of the study is not on the new coronavirus, the team says the same mechanism may also be present in the new coronary pneumonia caused by the virus. The link may also explain why people with diabetes are at higher risk of dying from the virus.
When a virus infects cells, it steals their resources in order to replicate itself, said Paul Thomas, an immunologist at St. Jude Children’s Research Hospital in Memphis, Tennessee, who was not involved in the new study. Infected cells must speed up metabolism to replenish these resources, and healthy cells must do so in order to produce an effective immune response. “
Immune changes at the molecular level
Scientists have long known that viral infections affect the metabolism of human cells. Previous studies have shown that influenza viruses increase glucose metabolism, involving a signaling protein called IRF5 (interferon regulator), which causes cytokine storms. In the latest study, the team detailed at the molecular level how this glucose metabolism causes the immune response to spiral out of control.
When cells become infected with the virus, high levels of glucose in the blood cause glycobaseization, and OGT enzymes bind to IRF5 and chemically modify them. This change triggers another chemical modification called ubiquitinization, which leads to an inflammatory response.
In the experiment, the researchers infected mice with the influenza A virus and then gave glucosamine to initiate this glucose metabolism pathway. They found that doing so could lead to a surge in cytokines. Next, they genetically modified the mice to lack the genes that produce ogT enzymes. When exposed to glucosamine, these mice did not produce excessive cytokine reactions.
Finally, the scientists analyzed the blood collected from patients with the Wuhan flu and healthy people from 2018 to 2019. They found that flu patients had higher levels of glucose in their blood and higher levels of immune system signal molecules than healthy people. This result further supports the idea that glucose metabolism plays a role in influenza infection.
How intervention can be used to avoid over-reaction
The results suggest that interfering with this glucose metabolism may be a way to prevent immune over-reactions from other viral infections, such as flu and new coronary pneumonia. However, such interventions need to be done with caution to avoid completely shutting down the body’s ability to fight the virus completely.
“This may be related to the use of chemical inhibitors to interfere with glucose metabolism and regulate the production of cytokines,” said study co-author Professor Lu Mengji of the Institute of Virology at the Essen School of Medicine in Germany. It should be noted, however, that energy metabolism plays an important role in our immune cells fighting viruses. It may be important to combine antiviral therapy with metabolic inhibitors to suppress the virus while reducing excessive immune responses. “
Professor Lu said: “Similar cytokine loss has also been observed in patients with new coronary pneumonia. But there are no specific drugs for the virus, so simply interfering with energy metabolism could cause our immune defenses to collapse without any benefit. “
Other researchers also praised the study. “This paper is a good example of the mechanism by which metabolic changes can trigger an inflammatory response,” Thomas said. “Previous studies have shown more broadly that glucose metabolism plays a role in responding to influenza infections. But he added that the paper details changes in the molecular level and how intervention in the process can prevent uncontrolled inflammation.
The findings confirm a 2018 study by Wen Haitao, an assistant professor of immunology at Ohio State University, and his colleagues. They found that using different RNA viruses produced the same metabolic response. A similar conclusion was reached in 2019 by another research team.
All three studies have shown that the transfer enzymes involved in this metabolic pathway need to initiate the host’s stress response to viral infections. “The initial purpose of this stress response is to create an immune response against pathogens and to try to fight the virus, ” says Professor Wen. But if the inflammatory response continues, it can cause additional damage. “
Will diet affect people’s new coronavirus response?
“It’s a very good question, but it’s too early to tell if a particular diet is resistant to viral infections, ” says Professor Wen. Scientists know that people with type 2 diabetes are more likely to be infected with the flu. But this risk is not because they have higher levels of glucose in their blood. The real reason is that they can’t use glucose effectively, so the antiviral response doesn’t start properly. “
The researchers hope that by interfering with this glucose metabolism pathway, a deadly cytokine storm can be avoided in patients with severe influenza or new coronary pneumonia. But Professor Lu’s team has yet to conduct human studies. “At the moment, we don’t have patient data to confirm the effects of interfering with glucose metabolism,” he said. It is too early to draw conclusions about its potential clinical applications. “