Purinergic signaling modulates immune function and is involved in the immunopathogenesis of several viral infections. This study aimed to investigate alterations in purinergic pathways in COVID-19 patients. Lower plasma ATP and adenosine levels were identified in mild and severe COVID-19 patients associated with proinflammatory cytokine profiles compared to healthy controls. Mild COVID-19 patients presented lower frequencies of CD4+CD25+CD39+ (activated/memory Treg) and CD4+CD25+CD39+CD73+ T cells, and increased frequencies of high differentiated (CD27-CD28-) CD8+T cells compared to health controls. Severe COVID-19 patients also showed higher frequencies of CD4+CD39+, CD4+CD25-CD39+ (memory T effector cell), high differentiated CD8+ T cells (CD27-CD28-) and diminished frequencies of CD4+CD73+, CD4+CD25+CD39+ mTreg, CD4+CD25+CD39+CD73+, CD8+CD73+ and low-differentiated CD8+ T cells (CD27+CD28+) in the blood in relation to mild COVID-19 patients and controls. Moreover, severe COVID-19 patients presented higher expression of PD-1 on low-differentiated CD8+ T cells. Both severe and mild COVID-19 patients presented higher frequencies of CD4+Annexin-V+ and CD8+Annexin-V+ T cells, showing increased T cell apoptosis. Plasma samples collected from severe COVID-19 patients were able to decrease the expression of CD73 on CD4+ and CD8+ T cells of a healthy donor. Interestingly, the in vitro incubation of PBMC from severe COVID-19 patients with adenosine reduced the NF-kB activation in T cells and monocytes. Together, these data add new knowledge regarding the immunopathology of COVID-19 through purinergic regulation, especially concerning adenosine deficiency. Brief CommentaryO_ST_ABSBackgroundC_ST_ABSHost factors modulates the type and the strength of the immune response during the viral infection, as well as the disease outcomes. However, to date, the role of purinergic signaling in SARS-CoV-2 infection remains unclear. We sought to evaluate alterations in extracellular adenine nucleotides and CD39/CD73 axis in T cells and their relationship with acute COVID-19 immunopathogenesis. Translational SignificanceCOVID-19 patients present lower extracellular ATP and adenosine levels associated with altered CD39 and CD73 expression in CD4+ and CD8+ T cells. Purinergic signaling correlated with alterations in the differentiation status of CD8+ T cells, lymphocyte mitochondrial membrane polarization and T cell apoptosis. Our demonstration of the lower NF-{kappa}B activation in T cells and monocytes after in vitro adenosine treatment may indicate the regulatory effect of adenosine in the inflammation and cytokine storm of COVID-19. This study adds new knowledge regarding the immunopathology of COVID-19 through purinergic regulation.
Alterations in CD39/CD73 Axis of T cells associated with COVID-19 severity