Severe COVID-19 associated with an imbalance in key immune system signaling

Researchers at 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 discovery helps explain at the molecular level why some people infected by SARS-CoV-2 develop a potentially fatal systemic inflammation. It also paves the way to the development of more specific therapies.

An article on the study, which was funded by FAPESP, is published in Frontiers in Immunology.

The researchers detected dysregulation of the immune system mediated by ATP (adenosine triphosphate), one of the main sources of energy for cellular processes. Severe COVID-19 patients had higher levels of ATP in their blood and lower levels of adenosine, which should increase when ATP is metabolized for energy production.

The immune system comprises 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 avoid excessive inflammation, but when this error in ATP metabolization occurs, it results in a huge imbalance and systemic dysfunctions in the immune response.”

Maria Notomi Sato, professor at USP’s Medical School and last author of the article

The increase in unmetabolized ATP, according to the article, produces a pro-inflammatory state and triggers a potentially fatal systemic inflammation known as a cytokine storm. “The study pointed to an imbalance in the signaling system and a dysfunction in the regulation of these components, as one more factor at the systemic level that attacks the organs of severe COVID-19 patients,” 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 exits cells in large amounts. When does that happen? When an exacerbated inflammatory response is activated, when cells are badly injured or when some other severe 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 article. She is a PhD candidate at the Virology Institute of Charité University Hospital Berlin in Germany.

Alteration in metabolization of ATP to adenosine

In the study, the 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 cell-surface ectonucleotidases that cleave ATP to be less expressed in cells from both mild and severe COVID-19 patients, but particularly the latter. In fact, we concluded that the higher the ATP level, the more severe the disease,” Pietrobon said.

The researchers also investigated possible alterations in immune system cells. “We found that some immune cells, especially B lymphocytes, 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 the levels of B cells in blood from severe patients were…