Brazilian Scientists Discover That Dysregulation Of The Immune System Mediated by Unmetabolized ATP Contributes To COVID-19 Severity!

Researchers from Brazil have discovered a new mechanism that contributes to COVID-19 disease severity. According to the study team lead by scientists from the University of São Paulo Medical School, unmetabolized ATP (adenosine triphosphate), a key source of energy for cellular processes causes the dysregulation of the immune system leading to cytokine storms that contributes to the disease severity.


 
The study team explained that ectonucleotidases modulate inflammatory responses by balancing extracellular ATP and adenosine (ADO) and might be involved in COVID-19 immunopathogenesis.
 
Ectonucleotidases consist of families of nucleotide metabolizing enzymes that are expressed on the plasma membrane and have externally oriented active sites. These enzymes metabolize nucleotides to nucleosides. Ectonucleotidases produce key molecules for purine salvage and consequent replenishment of ATP stores within multiple cell types. In addition, ectonucleotidases generate extracellular adenosine, which abrogates nucleotide-mediated effects and activates adenosine receptors, often with opposing (patho-) physiological effects.The first step in the production of adenosine involves the conversion of ATP/ADP to AMP. It is carried out by ENTPD1 (a type of Ectonucleotidases), also known as CD39. The second step involves the conversion of AMP to adenosine. It is carried out by NT5E, also known as CD73.
 
The study team explored the contribution of extracellular nucleotide metabolism to COVID-19 severity in mild and severe cases of the disease.
 
The researchers verified that the gene expression of ectonucleotidases is reduced in the whole blood of patients with COVID-19 and is negatively correlated to levels of CRP, an inflammatory marker of disease severity.
 
Hence, it was found that COVID-19 patients present higher ATP levels in plasma and reduced levels of ADO when compared to healthy controls.
 
Subsequent cell type-specific analysis revealed higher frequencies of CD39+ T cells in severely ill patients, while CD4+ and CD8+ expressing CD73 are reduced in this same group. The frequency of B cells CD39+CD73+ is also decreased during acute COVID-19.
 
Interestingly, B cells from COVID-19 patients showed a reduced capacity to hydrolyze ATP into ADP and ADO. Furthermore, impaired expression of ADO receptors and a compromised activation of its signaling pathway is observed in COVID-19 patients.
 
However, the presence of ADO in vitro suppressed inflammatory responses triggered in patients’ cells.
 
The study findings shows that alterations in the metabolism of extracellular purines contribute to immune dysregulation during COVID-19, possibly favoring disease severity, and suggest that ADO may be a therapeutic approach for the disease.
 
The study findings were published in the peer reviewed journal: Frontiers Of Immunology.
https://www.frontiersin.org/articles/10.3389/fimmu.2022.1012027/full
 
The study findings confirm that 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 individuals infected by SARS-CoV-2 develop a potentially fatal systemic inflammation. It also paves the way to the development of more specific t herapies.
 
The study team 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.
 
Co-researcher, Dr Maria Notomi Sato, a Professor at University of Sao Paulo's Medical School told Thailand Medical News, "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 [metabolism] occurs, it results in a huge imbalance and systemic dysfunctions in the immune response.”
 
Interestingly, the increase in unmetabolized ATP produces a pro-inflammatory state and triggers a potentially fatal systemic inflammation known as a cytokine storm.
 
Dr Sato further added, "The research findings 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.”
 
Adenosine triphosphate or ATP is constantly produced by cells and is broken down in the extracellular environment by enzymes called ectonucleotidases.
 
The study team added, "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."
 
The study team 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.
 
The study team commented, "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.”
 
The study team also investigated possible alterations in immune system cells.
 
They said, "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 low, but these cells also expressed lower amounts of both enzymes, contributing to less ATP [metabolism] and hence less production of adenosine, the anti-inflammatory component that would try to regulate this response.”
 
Considering this finding, the study team decided to isolate the B cells present in the blood samples and provide them with ATP.
 
Dr Sato added, "We conducted an in vivo experiment in which we gave ATP to cells from both COVID-19 patient and healthy controls. The B cells from patients produced less adenosine than those from the healthy controls, possibly because they expressed less CD39 and CD73.”
 
The study team noted that they do not yet know if the alteration in ATP metabolism causes or is caused by the exacerbated inflammatory response to SARS-CoV-2. They plan to investigate this in future projects.
 
A past study conducted at the Center for Research on Inflammatory Diseases (CRID) had already detected a link between severe COVID-19 and inflammasome activation, which in these patients is exacerbated and fails to shut down after the infection clears.
 
Inflammasomes are protein complexes inside defense cells. When this cellular mechanism is activated, pro-inflammatory molecules known as cytokines are produced to warn the immune system that more defense cells need to be sent to the infection site.
 
The study team says that the buildup of ATP in conjunction with low levels of adenosine in severe patients may contribute to exacerbation of the cytokine-mediated inflammatory response.
 
Dr Sato added, "The inflammatory process triggered by insufficient ATP breakdown occurs because of decompensation in this pathway, which functions as a form of anti-inflammatory regulation. However, when this error in the ATP-adenosine metabolism occurs, the ATP build-up acts as a signal to other inflammation pathways in the immune system, culminating in inflammasome activation, for example.”
 
In such cases, in which immune system regulation is dysfunctional, the excessive inflammatory response is directly linked to multiple organ failure and frequently to death.
 
Finding new therapeutic strategies to overcome these issues could be a new way to treat severe COVID-19 and also help save lives.
 
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