Scientists have found that many of those who die from the new coronavirus appear to be harmed more by the autoimmune system than by the virus itself.
Viral infection triggers a "cytokine storm", a surge in cell signaling proteins. This triggers inflammation, damages lungs and body tissues, and can lead to organ failure and death.
However, this phenomenon is not unique to patients with novel coronavirus pneumonia and is sometimes seen in patients with severe influenza. A new study reveals the metabolic mechanisms that lead to this uncontrolled inflammatory phenomenon.
Viral infections can affect glucose metabolism
In a paper published in the journal Science Advances, researchers say that infection of live mouse and human cells with influenza A virus triggers a series of cellular activities that open a pathway for glucose metabolism.
These changes, in turn, lead to the production of a large number of cytokines, so blocking a key enzyme in glucose metabolism has the potential to prevent a lethal cytokine surge.
Interleukin 4, the cytokine that triggers allergic reactions
Although the study did not focus on a novel coronavirus, the team said the same mechanism may be present in the novel coronavirus pneumonia caused by this virus.
This link could also explain why people with diabetes are at a higher risk of dying from this virus.
Paul Thomas, an immunologist at St. Jude Children's Research Hospital in Memphis, Tennessee, who was not involved in the new study, explained that when a virus infects cells, it steals their resources in order to replicate itself. Infected cells must speed up their metabolism to replenish these resources, and healthy cells must do the same in order to produce an effective immune response."
Immune changes at the molecular level
It has long been known to scientists that viral infections affect the metabolism of human cells.
Previous studies have shown that infection with influenza viruses increases glucose metabolism, which involves a signaling protein called IRF5 (interferon regulatory factor), which causes a cytokine storm.
In the latest study, the team revealed in detail at the molecular level how this glucose metabolism leads to an uncontrolled immune response.
When cells are infected with a virus, high levels of glucose in the blood cause glycosylation, and the OGT enzyme binds to IRF5 and chemically modifies it. This change triggers another chemical modification called ubiquitination, which leads to an inflammatory response.
In the experiment, researchers infected mice with the influenza A virus and then gave glucosamine to initiate this glucose metabolism pathway. They found that this led to a surge in cytokines.
Next, they genetically modified the mice so that they lacked the gene that produces OGTase. When exposed to glucosamine, these mice did not produce an excessive cytokine response.
Finally, the scientists analyzed blood collected from patients with 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 signaling molecules compared to healthy people. This result further supports the idea that glucose metabolism plays a role in influenza infection.
How to intervene to avoid an immune overreaction
The results of this study suggest that interfering with this glucose metabolism may be a way to prevent an immune overreaction to other viral infections such as influenza and novel coronavirus pneumonia in patients.
However, such an intervention needs to be carried out carefully to avoid completely shutting down the body's ability to fight the virus.
The study's co-author, Professor Lu Mengji of the Institute of Virology at the Essen Medical School in Germany, said: "This may be related to the use of chemical inhibitors that interfere with glucose metabolism and regulate cytokine production. It should be noted, however, that energy metabolism plays an important role in our immune cells' fight against viruses. It may be important to use a combination of antiviral therapy and metabolic inhibitors to suppress the virus while reducing excessive immune responses."
A similar phenomenon of cytokine runaway has been observed in patients with novel coronavirus pneumonia," according to Professor Lu. But there are currently no specific drugs that target the virus that causes it, so simply interfering with energy metabolism could cause our immune defense system to collapse and not bring any benefit."
Other researchers also praised the study, and Thomas said, "This paper does a good job of proposing and validating the mechanisms by which metabolic changes can cause an inflammatory response." Previous studies have more extensively shown that glucose metabolism plays a role in response to influenza infection. But he added that the paper details the changes at the molecular level and how intervening in this process can prevent uncontrolled inflammation from occurring.
These findings confirm a 2018 study by Wen Haitao, assistant professor of immunology at The Ohio State University, and his colleagues. They found that using different RNA viruses produced the same metabolic response, and another team of researchers in 2019 came to a similar conclusion.
All three studies suggest that transferases involved in this metabolic pathway are required to initiate a host stress response to viral infection. According to Professor Wen, "The original purpose of this stress response was to establish an immune response against the pathogen and to try to fight the virus. But if the inflammatory response continues, additional damage can be done."
Does diet affect people's response to novel coronavirus infections?
Professor Wen said: "This is a very good question, but it is too early to conclude whether a particular diet is resistant to viral infection. Scientists are well aware that people with type 2 diabetes are more susceptible to serious flu infections. But this risk isn't because they have higher glucose levels in their blood. The real reason is that they can't use glucose effectively, so the antiviral response doesn't kick in."
By interfering with this glucose metabolism pathway, the researchers hope to avoid a deadly cytokine storm in patients with severe influenza or novel coronavirus pneumonia.
But Professor Lu's team has yet to conduct human studies. He said: "Currently, we do not have patient data to confirm the effects of interfering with glucose metabolism. It is too early to draw conclusions about its potential clinical applications."
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