Researchers from the University of São Paulo (USP) in Brazil have found that severe COVID-19 is associated with an imbalance in an important immune system signaling pathway. The finding helps explain at the molecular level why some people infected with SARS-CoV-2 develop life-threatening systemic inflammation. It also paves the way for the development of more specific therapies.
An article on the study funded by FAPESP is published in Frontiers in immunology.
The researchers detected a dysregulation of the immune system 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 increase when ATP is metabolized for energy production.
The immune system includes several signaling pathways that provide alerts in response to invasion by a pathogen, for example. One involves ATP, which triggers the release of inflammatory substances in defense cells to attack the invader. The immune system also has control mechanisms to prevent excessive inflammation, but when this error in ATP metabolism occurs, it leads to a huge imbalance and systemic dysfunctions in the immune response.”
Maria Notomi Sato, professor at USP School of Medicine and final author of the paper
The increase in unmetabolized ATP, according to the article, produces a pro-inflammatory state and triggers a life-threatening systemic inflammation known as a cytokine storm. “The study highlighted an imbalance in the signaling system and a dysfunction in the regulation of these components, as one more systemic level factor that attacks the organs of patients with severe COVID-19,” Sato said. .
ATP is constantly produced by cells and is broken down in the extracellular environment by enzymes called ectonucleotidases. “ATP turns into a danger signal when it leaves cells in large quantities. When does this happen? When an exacerbated inflammatory response is activated, when cells are severely injured, or when other serious damage occurs. In response, ATP triggers an inflammatory process that involves other cells in a chain reaction,” said Anna Julia Pietrobon, first author of the paper. She is a PhD candidate at the Institute of Virology at Charité University Hospital in Berlin, Germany.
Altered metabolism of ATP to adenosine
In the study, researchers measured ATP and adenosine levels in blood samples from 88 patients with severe COVID-19 collected in 2020-21. None of the patients had been vaccinated.
“We found that cell surface ectonucleotidases that cleave ATP are less expressed in cells from mild and severe COVID-19 patients, but particularly from the latter. In fact, we concluded that the higher the level of ATP, the more severe the disease,” says Pietrobon.
The researchers also studied possible alterations in cells of the immune system. “We found that some immune cells, particularly B cells, expressed less CD39 and CD73, enzymes that break down ATP. Lymphocyte levels generally tend to be low in COVID-19 patients, but in our study, not only were B cell levels in the blood of severe patients low, but these cells also expressed lower amounts of both enzymes. , contributing to less ATP metabolism and therefore less production of adenosine, the anti-inflammatory component that would attempt to regulate this response,” said Pietrobon.
Faced with this discovery, the researchers decided to isolate the B lymphocytes present in the blood samples and supply them with ATP. “We conducted an in vivo experiment in which we gave ATP to cells from COVID-19 patients and healthy controls. B cells from patients produced less adenosine than those from healthy controls, possibly because they expressed less CD39 and CD73,” she added. said.
It should be noted that researchers do not yet know if the impaired ATP metabolism causes or is caused by the heightened inflammatory response to SARS-CoV-2. They plan to study this in future projects.
Systemic reaction
A study conducted at the Center for Research on Inflammatory Diseases (CRID) had already detected a link between severe COVID-19 and the activation of the inflammasome, which in these patients is exacerbated and fails to stop after the disappearance of the infection (find out more at: agencia.FAPESP.br/39411).
CRID is a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP and hosted by USP’s Ribeirão Preto Medical School.
The inflammasome is a protein complex inside defense cells. When this cellular mechanism is activated, pro-inflammatory molecules called cytokines are produced to alert the immune system that more defense cells need to be sent to the site of infection.
According to the researchers who conducted the ATP Metabolization Study, the accumulation of ATP in conjunction with low levels of adenosine in severe patients may contribute to the exacerbation of the cytokine-mediated inflammatory response. . “The inflammatory process triggered by insufficient degradation of ATP occurs due to the decompensation of this pathway, which functions as a form of anti-inflammatory regulation. However, when this error in ATP-adenosine metabolism occurs, the accumulation of ATP acts as a signal. to other immune system inflammation pathways, culminating in inflammasome activation, for example,” Sato said.
In these cases, where the regulation of the immune system is dysfunctional, the excessive inflammatory response is directly linked to multi-organ failure and frequently to death.