Brazilians discover reasons for more serious cases

Researchers from the University of Sao Paulo (USP) have found that the severe form of COVID-19 is associated with an imbalance in an important signaling pathway in the immune system. In addition to helping explain at the molecular level why some people infected with SARS-CoV-2 develop potentially fatal systemic inflammation, the discovery paves the way for the development of more specific therapies.

The study – funded by FAPESP and published in the journal Frontiers in Immunology – has identified the presence 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 process. cell phones.

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In addition to having a higher amount of ATP in their blood, patients with the severe form of the disease had a lower amount of adenosine, a molecule generated by the breakdown of ATP.

“The immune system is made up of different signaling pathways that serve, for example, to warn of the invasion of a pathogen. Among them, there is one that works by means of ATP molecules, which release inflammatory signals in defense cells as a means of attacking the invader. In general, the immune system also has mechanisms to control this inflammation, thus preventing a highly 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, a professor at the USP School of Medicine and co-author of the study.

This increase in non-degraded ATP, according to the paper, results in a pro-inflammatory state 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 the systemic level or in the organs affected by severe COVID-19, ”says Sato.

ATP is a molecule that is constantly produced by cells and is broken down in the extracellular environment by enzymes called ectonucleotidases. “ATP becomes a warning sign from the moment it leaves cells in large numbers. And when does it happen? When exacerbated activation occurs [da resposta inflamatória], or when the cell has been badly 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 PhD student at the Institute of Virology of the Charité Universitätsmedizin in Berlin (Germany).

Alteration of the ATP-adenosine axis

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

“We identified that cell surface ectonucleotidases that are responsible for ATP cleavage were less expressed in the cells of COVID patients, especially in the severe form of the disease. We also found a relationship: the more ATP, the greater the severity of the disease, ”says Pietrobon.

The researchers also studied possible changes in the cells of the immune system. “We observed that some immune cells, particularly B lymphocytes, expressed 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 the blood samples of critically ill patients, in addition to the decrease in B lymphocytes, they also expressed less of these two enzymes, which contributes to reducing the degradation of ATP and, consequently, to reducing the generation of adenosine. the anti-inflammatory component that would try to regulate that response, ”Pietrobon explained.

With this discovery, the researchers set out to isolate the B lymphocytes present in the blood samples and supply them with ATP molecules. “In the in vitro experiment, we administered ATP to both cells from COVID-19 patients and healthy controls. In this way, we found that the patients ‘B cells generate less adenosine than healthy controls. This is likely due to the fact that the patients’ B cells generate less adenosine than healthy controls. they express fewer CD39 and CD73 enzymes, ”he says.

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

Systemic reaction

Another work done at the Center for Research in Inflammatory Diseases (CRID) – a Center for Research, Innovation and Dissemination (CEPID) of FAPESP based at the USP in Ribeirão Preto – had already found that the most serious condition of COVID- 19 is related to an inflammatory mechanism known as an 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 on: agencia.fapesp.br/39333/).

The inflammasome is a protein complex that exists within defense cells. When this cellular mechanism is activated, pro-inflammatory molecules known as cytokines are produced to alert the immune system to the need to send more defense cells to the site of infection.

The team of researchers who conducted the ATP metabolism study states that the fact that critically ill patients accumulate this molecule and generate 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 functions as a form of anti-inflammatory regulation. However, when this error occurs in the ATP-adenosine axis, the ATP overload will signal other pathways of inflammation in the immune system, culminating, for example, in the activation of the inflammasome, “says Sato.

Not surprisingly, 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 multi-organ failure, factors that lead to the worst outcomes of COVID-19.

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