New mechanism associated with the worsening of Covid-19 discovered

Researchers from USP (University of São Paulo) found 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 the molecular level why part of those infected with SARS-CoV-2 develop potentially fatal systemic inflammation, the finding opens the way for the development of more specific therapies.

The study —funded by Fapesp and published in the journal Frontiers in Immunology— identified the occurrence of a deregulation in the signaling system of the immune response mediated by molecules of ATP (adenosine triphosphate), one of the main sources of energy for carrying out the processes cell phones. 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 degradation of ATP.

“The immune system is made up of several signaling pathways that serve to warn about 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 attack 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 ATP degradation, there is a huge imbalance that triggers systemic dysfunctions in the immune response”, explains Maria Notomi Sato, professor at the USP School of Medicine and co-author of the study.

This increase in undegraded ATP, according to the paper, results in a pro-inflammatory status that triggers a 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 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 as soon as it leaves the cells in large quantities. And when does that happen? When does an exacerbated activation occur? [da resposta inflamatória], or when the cell has been seriously injured, or when there is very great damage. ATP then promotes an inflammatory process that signals the other cells, activating them as a chain reaction,” says Anna Julia Pietrobon, first author of the study and a PhD candidate at the Institute of Virology at the 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, this 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 immune system cells. “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 reduced lymphocytes in general. However, we observed that in blood samples from critically ill patients, in addition to the decrease in B cells, they also expressed less of these two enzymes, which contributes to the lower ATP degradation and, consequently, to the lower 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 the cells of Covid-19 patients and healthy controls. In this way, we found that the patients’ B cells generate less adenosine compared to healthy controls. This is possibly the case. because they express less CD39 and CD73 enzymes”, he says.

It is worth mentioning that the research team does not yet know whether the alteration in ATP metabolism is a cause or an effect of the exacerbated inflammatory response to SARS-CoV-2, something that still needs to be investigated in future projects.

Systemic reaction

Another work carried out at CRID (Center for Research in Inflammatory Diseases) —a CEPID (Center for Research, Innovation and Diffusion) of Fapesp based at USP in Ribeirão Preto— had already found that the most serious condition of Covid-19 is related to a 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 here).

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

The team of researchers that carried out the study on ATP metabolism says that the fact that critically ill patients are accumulating this molecule and generating less adenosine may contribute to the exacerbation of cytokine-mediated inflammatory responses.

“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 to other pathways.” of inflammation of 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.

The article Dysfunctional purinergic signaling correlates with disease severity in Covid-19 patients can be read here.