Dysfunctional purinergic signaling correlates with disease severity in COVID-19 patients

Abstract

Ectonucleotidases modulate inflammatory responses by balancing extracellular ATP and adenosine (ADO) and might be involved in COVID-19 immunopathogenesis. Here, we explored the contribution of extracellular nucleotide metabolism to COVID-19 severity in mild and severe cases of the disease. We 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. In line with these findings, COVID-19 patients present higher ATP levels in plasma and reduced levels of ADO when compared to healthy controls. 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. The presence of ADO in vitro, however, suppressed inflammatory responses triggered in patients’ cells. In summary, our findings support the idea 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 Role of Cluster of Differentiation 39 (CD39) and Purinergic Signaling Pathway in Viral Infections

“…The percentage of CD39+ cells in CD4+ and CD8+ T lymphocytes was higher in severe SARS-CoV2-infected patients than in mild patients and healthy individuals, but the percentage of CD39+ in monocytes (CD39+ CD14+) among these groups was comparable [ 52 ]. Nevertheless, this trend was not detected in CD73+ T cells among these groups [ 52 ].…”

“…The percentage of CD39+ cells in CD4+ and CD8+ T lymphocytes was higher in severe SARS-CoV2-infected patients than in mild patients and healthy individuals, but the percentage of CD39+ in monocytes (CD39+ CD14+) among these groups was comparable [ 52 ]. Nevertheless, this trend was not detected in CD73+ T cells among these groups [ 52 ]. The gene expression of several ectonucleotidase transcripts associated with CD39 (ENPP1, ENPP2, and ENPP3) was lower in severely infected patients than in controls [ 52 ].…”

“…Nevertheless, this trend was not detected in CD73+ T cells among these groups [ 52 ]. The gene expression of several ectonucleotidase transcripts associated with CD39 (ENPP1, ENPP2, and ENPP3) was lower in severely infected patients than in controls [ 52 ]. The frequency of CD39+ in B lymphocytes was reduced in severe COVID-19 infection [ 52 ].…”

“…The gene expression of several ectonucleotidase transcripts associated with CD39 (ENPP1, ENPP2, and ENPP3) was lower in severely infected patients than in controls [ 52 ]. The frequency of CD39+ in B lymphocytes was reduced in severe COVID-19 infection [ 52 ]. Another study revealed that the plasma concentration of soluble CD39 was elevated in COVID-19 patients and was associated with the length of hospital stay [ 55 ].…”

Characterization of Regulatory T Cells in Patients Infected by Leishmania Infantum

“…However, studies also show that changes in the CD39 and CD73 expression by lymphocytes or other cells can be correlated with distinct clinical profile in a variety of diseases [ 13 , 14 , 15 ]. These changes in ectonucleotidases levels can impact the purinergic metabolism reflecting in the adenosine availability [ 16 ].…”