University of São Paulo: New mechanism associated with the worsening of covid-19 discovered

Researchers from USP discovered that the severe form of covid-19 is associated with an imbalance in an important signaling pathway of the immune system. In addition to helping to explain at a molecular level why part of those infected with sars-cov-2 develop potentially fatal systemic inflammation, the finding paves the way for the development of more specific therapies.

In the study – funded by the State of São Paulo Research Foundation (FAPESP) and published in the journal Frontiers in Immunology – the occurrence of a deregulation in the signaling system of the immune response mediated by ATP (adenosine triphosphate) molecules was identified. , one of the main sources of energy for carrying out cellular processes. In addition to having a higher amount of ATP in the blood, patients with the severe form of the disease had a lower amount of adenosine, a molecule generated from the breakdown of ATP.

“The immune system is made up of several signaling pathways that serve to warn of the invasion of a pathogen, for example. Among them, there is one that works through ATP molecules, which release inflammatory signals in defense cells as a way of attacking the invader. Generally, the immune system also has mechanisms to control this inflammation, thus avoiding a very exacerbated response. However, when this error occurs in the degradation of ATP, there is a huge imbalance that triggers systemic dysfunctions in the immune response”, explains Maria Notomi Sato , professor at the Faculty of Medicine of USP (FMUSP) and co-author of the study.


This increase in undegraded ATP, according to the article, results in a pro-inflammatory status that triggers the so-called cytokine storm, a potentially fatal systemic inflammation. “The study shows that, in addition to contributing to the imbalance of the signaling system, there is a dysfunction in the regulation of these components. It is one more of the factors that will act at a systemic level or in the organs affected by severe covid-19”, says Sato.

ATP is a molecule that is constantly being produced by cells and is degraded in the extracellular environment by enzymes called ectonucleotidases. “ATP becomes a danger signal from the moment it leaves the cells in large quantities. And when does that happen? When there is an exacerbated activation [of the inflammatory response] , or when the cell has been seriously injured, or even when there is a very large amount of damage. ATP then promotes an inflammatory process that signals to other cells, activating them like a chain reaction,” says Anna Julia Pietrobon , first author of the study and PhD student at the Institute of Virology at Charité Universitätsmedizin Berlin (Germany).

Alteration in the ATP-adenosine axis

In the study, researchers measured the amount of ATP and adenosine molecules in blood samples from 88 patients with severe covid-19. Samples were collected between 2020 and 2021 and therefore none of the participants had been vaccinated.

“We identified that ectonucleotidases present on the cell surface and which are responsible for cleaving ATP were less expressed in the cells of patients with covid, mainly in the severe form of the disease. We even identified a relationship: the more ATP, the greater the severity of the disease”, says Pietrobon.

The researchers also investigated possible changes in cells of the immune system. “We observed that some immune cells, especially B lymphocytes, were expressing less CD39 and CD73, enzymes that degrade ATP”, said the researcher.

“Patients with covid-19 tend to have a reduction in lymphocytes in general. However, we observed that in blood samples from critically ill patients, in addition to the fact that B cells were reduced, they also expressed less of these two enzymes, which contributes to less degradation of ATP and, consequently, to less generation of adenosine – the anti-inflammatory component that would try to regulate this response”, explained Pietrobon.

With this finding, the researchers decided to isolate the B cells present in the blood samples and provide them with ATP molecules. “In the in vitro experiment , we gave ATP to both cells from patients with Covid-19 and those from healthy controls. Thus, we found that B cells from patients generate less adenosine compared to healthy controls. This happens possibly because they express less CD39 and CD73 enzymes”, he says.

It is worth noting that the team of researchers still does not know whether the alteration in ATP metabolism is a cause or effect of the exacerbated inflammatory response to sars-cov-2, something that still needs to be investigated in future projects.

Another study carried out at the Center for Research in Inflammatory Diseases ( CRID ) – a Fapesp Research, Innovation and Dissemination Center ( Cepid ) based on USP’s Ribeirão Preto campus – had already found that the most serious condition of covid-19 is related to with an inflammatory mechanism known as inflammasome, which, in addition to being exacerbated in these critically ill patients, is never deactivated. In this way, the immune response that causes inflammation also does not cease ( read more at: agencia.fapesp.br/39333/ ).

The inflammasome is a protein complex found inside defense cells. When this cellular machinery is triggered, pro-inflammatory molecules known as cytokines are produced to warn the immune system about the need to send more defense cells to the site of infection.

The team of researchers who carried out the study on ATP metabolism states that the fact that critically ill patients are accumulating this molecule and generating less adenosine may contribute to the exacerbation of inflammatory responses mediated by cytokines. “The inflammatory process triggered by the non-degradation of ATP occurs due to a decompensation of this pathway, which works as a form of anti-inflammatory regulation. However, when this error occurs in the ATP-adenosine axis, the ATP overload will signal other inflammation pathways in the immune system, culminating in the activation of the inflammasome, for example”, says Sato.

Not by chance, according to the researchers, it is in these cases where the regulation of the immune system is dysfunctional that an exaggerated inflammatory response occurs and is directly related to multiple organ failure – factors that lead to the worst outcomes of covid-19.