Washington: Scientists have uncovered a new mechanism that could help explain why some Covid-infected people develop potentially deadly systemic inflammation, according to a study.
Researchers at the University of Sao Paulo (USP) in Brazil have found that severe COVID-19 disease is associated with an imbalance in a key immune system signaling pathway.
The researchers discovered a “dysregulation”, i.e. a disturbed regulation of the immune system, mediated by adenosine triphosphate (ATP), one of the main energy sources for cellular processes.
Severe COVID-19 patients had higher levels of ATP in their blood and lower levels of adenosine, which should increase as ATP is metabolized for energy, the study said.
“The immune system consists of several signaling pathways that, for example, sound the alarm when a pathogen invades. One concerns ATP, which triggers the release of inflammatory substances in defense cells to attack the invader,” said study author Maria Notomi Sato.
“The immune system also has control mechanisms to avoid excessive inflammation, but when this error occurs in ATP metabolism, it leads to tremendous imbalance and systemic dysfunction in the immune response,” Sato said.
The increase in unmetabolized ATP leads to a pro-inflammatory state, according to the study, triggering a potentially deadly systemic inflammation known as a cytokine storm.
“The study pointed to an imbalance in the signaling system and dysfunction in the regulation of these components as another factor at the systemic level attacking the organs of severe COVID-19 patients,” said Sato.
ATP is constantly being produced by cells and broken down in the extracellular environment by enzymes called ectonucleotidases.
“ATP becomes a danger signal when it leaves cells in large quantities. when does this happen When an enhanced inflammatory response is activated, when cells are severely injured, or when other severe damage occurs,” said Anna Julia Pietrobon, co-study author of the article.
“In response, ATP triggers an inflammatory process that involves other cells in a chain reaction,” says Pietrobon.
For the study, researchers measured ATP and adenosine levels in blood samples taken from 88 patients with severe COVID-19 in 2020-21. None of them were vaccinated.
“We found that cell-surface ectonucleotidases that cleave ATP are expressed less in cells from both mild and severe COVID-19 patients, but especially the latter. In fact, we concluded that the higher the ATP level, the more severe the disease,” Pietrobon said.
The researchers also looked at possible changes in cells of the immune system.
“We found that some immune cells, particularly B lymphocytes, expressed less CD39 and CD73, enzymes that break down ATP.
“Lymphocyte levels are generally low in COVID-19 patients, but in our study, not only were B cell levels in the blood of patients with severe disease low, but these cells also expressed lower levels of both enzymes, resulting in lower ATP metabolism, and therefore less production of adenosine, the anti-inflammatory component that would try to regulate this response,” Pietrobon said.
Based on this finding, the researchers decided to isolate the B cells present in the blood samples and supply them with ATP.
“We performed an in vivo experiment where we administered ATP to cells from COVID-19 patients and healthy controls. Patients’ B cells produced less adenosine than healthy controls, possibly because they expressed less CD39 and CD73,” she said.
Researchers do not yet know whether the alteration in ATP metabolism causes or is caused by the increased inflammatory response to SARS-CoV-2. They plan to investigate this in future projects, the study said.
The association between severe COVID-19 and inflammasome activation is being tightened and cannot be switched off once the infection has resolved.
The inflammasome is a protein complex within immune cells. When this cellular mechanism is activated, pro-inflammatory molecules called cytokines are produced to alert the immune system to send more defense cells to the site of infection.
According to the researchers who conducted the ATP metabolism study, the buildup of ATP coupled with low adenosine levels may contribute to exacerbating the cytokine-mediated inflammatory response in severe patients.
“The inflammatory process triggered by insufficient ATP breakdown occurs due to decompensation in this pathway, which acts as a form of anti-inflammatory regulation.
“However, when this error occurs in ATP-adenosine metabolism, the ATP buildup acts as a signal for other inflammatory pathways in the immune system, culminating in activation of inflammasome, for example,” Sato said.
In these cases, where regulation of the immune system is disrupted, the excessive inflammatory response is directly linked to multiple organ failure and often death.
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