Researchers at the University of São Paulo (USP) in Brazil discovered that severe COVID-19 is linked to an imbalance in a vital signaling pathway of the immune system. The discovery is helping at the molecular point by which some other people became inflamed with SARS-CoV-2 expands life-threatening systemic inflammation. It also paves the way for the progression of faster therapies.
An article about the FAPESP-funded project is published in Frontiers in Immunology.
The researchers detected a dysregulation of the immune formula mediated by ATP (adenosine triphosphate), one of the main sources of energy for cellular processes. Patients with severe COVID-19 had higher levels of ATP in their blood and lower levels of adenosine, which are expected to accumulate when ATP is metabolized for energy production.
The immune formula includes several signaling pathways that provide alerts in reaction to an invasion via a pathogen, for example. One comes to ATP, which triggers the release of inflammatory ingredients into defense cells to attack the invader. The immune formula also has mechanisms to save over-inflammatory, but when this error in ATP metabolism occurs, it leads to massive imbalance and dysfunctions formulated in the immune reaction. “
The accumulation of unmetabolized ATP, according to the article, produces a pro-inflammatory state and triggers a potentially deadly formulated inflammation known as cytokine storm. as one more thing at the point of formula that attacks the organs of patients with severe COVID-19,” Sato said.
ATP is constantly produced through cells and is damaged in the extracellular environment through enzymes called ectonucleotidases. ATP becomes a danger signal when it leaves cells in gigantic amounts. When does this happen? When an exacerbated inflammatory reaction is triggered, when cells are severely injured, or when other serious damage occurs. In reaction, ATP triggers an inflammatory process that reaches other cells in a chain reaction,” said Anna Julia Pietrobon, first of the paper. She is a PhD candidate at the Institute of Virology at the Charité University Hospital in Berlin, Germany.
In the study, researchers measured ATP and adenosine levels in blood samples from 88 severe COVID-19 patients collected in 2020-21. None of the patients had been vaccinated.
“We found that PTA-cleave-cleaving motile ectonucleotidases are less expressed in the mobiles of patients with mild and severe COVID-19, but in the latter. In fact, we concluded that the higher the ATP point, the more severe the disease. “says Pietrobon.
The researchers also studied imaginable alterations in the cells of the immune formula. We found that some immune cells, namely B cells, expressed less CD39 and CD73, enzymes that break down ATP. Lymphocyte levels sometimes tend to be low in COVID-19 patients. however, in our study, not only were B cell levels in the blood of critically ill patients low, but those cells also expressed lower amounts of either enzyme, contributing to lower ATP metabolism and therefore lower adenosine production. check to regulate this response,” Pietrobon said.
Faced with this discovery, the researchers isolated the B cells they contribute in the blood samples and gave them ATP. “We conducted an in vivo experiment in which we gave ATP to cells from COVID-19 patients and healthy controls. B cells produced less adenosine than those in healthy controls, most likely because they expressed less CD39 and CD73. “
It should be noted that researchers do not yet know whether the impairment of ATP metabolism is due to or due to the exacerbated inflammatory reaction to SARS-CoV-2. They plan to examine this in long-term projects.
A study conducted at the Inflammatory Diseases Research Center (CRID) had already detected a link between severe COVID-19 and the activation of the inflammasome, which in these patients is exacerbated and prevents after the disappearance of the infection (read more at: agencia. fapesp. br/39411).
CRID is a research, innovation and dissemination project (RIDC) funded through FAPESP and hosted at USP’s Ribeirão Preto School of Medicine.
The inflammasome is an internal protein complex of defense cells. When this cellular mechanism is activated, pro-inflammatory molecules called cytokines are produced to warn the immune formula that more defense cells want to be sent to the site of infection.
According to the researchers who conducted the ATP metabolism study, ATP accumulation along with low adenosine levels in critically ill patients could contribute to cytokine-mediated exacerbation of the inflammatory response. to the decompensation of this pathway, which functions as a form of anti-inflammatory regulation. However, when this error occurs in ATP-adenosine metabolism, ATP accumulation acts as a signal to other immune system inflammation pathways, culminating in inflammasome activation, for example,” Sato said.
In those cases, where the regulation of the immune formula is dysfunctional, the exaggerated inflammatory reaction is directly similar to multi-organ failure and death.
São Paulo Research Foundation (FAPESP)
Pietrobon, AJ, et al. (2022) Dysfunctional purinergic signaling correlates with severity in COVID-19 patients. Borders in immunologie. doi. org/10. 3389/fimmu. 2022. 1012027.
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