High levels of extracellular ATP lead to different inflammatory responses in COVID-19 patients according to the severity

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has significantly impacted the world and has driven many researchers into the pathophysiology of COVID-19. In the findings, there is a close association between purinergic signaling and the immune response. Then, this study aimed to evaluate alterations in the purinergic signaling in COVID-19 patients according to range severity. We divided the COVID-19 patients into moderate and severe cases following the guideless of NIH and WHO, together with clinical characteristics. The blood samples were collected to obtain PBMCs and platelets. We analyzed the ectonucleotidase activities through ATP, ADP, AMP, Ado hydrolysis, E-NTPDase1 (CD39), and 5′-NT (CD73) expression by flow cytometry in total leukocytes. The extracellular ATP was measured by bioluminescence, and cytokines were analyzed by flow cytometry. We observed a decrease in ATP hydrolysis and increased AMP hydrolysis in PBMCs for both groups. In severe cases, ATP hydrolysis was raised for the platelets, while ADP and AMP hydrolysis have risen significantly in both groups. Additionally, there was a significant increase in ADP hydrolysis in severe cases compared to moderate cases. In addition, we observed an increase in the ADA activity in platelets of moderate patients. Moderate and severe cases showed increased expression of CD39 and CD73 in total leukocytes. To finalize the purinergic signaling, extracellular ATP was increased in both groups. Furthermore, there was an increase in IL-2, IL-6, IL-10, and IL-17 in moderate and severe groups. Thus, for the first time, our findings confirm the changes in purinergic signaling and immune response in COVID-19, in addition to making it more evident that the severity range directly impacts these changes. Therefore, the therapeutic potential of the purinergic system must be highlighted and studied as a possible target for the treatment of SARS-CoV-2 disease. Key messages COVID-19 patients exhibit alterations in purinergic system and immune response. High levels of extracellular ATP lead to different inflammatory responses. CD39 and CD73 expression were increased in COVID-19 patients. Cytokines IL-2, IL-6, IL-10, and IL-17 also were altered in these patients. The purinergic system may be a possibility target to SARS-CoV-2 treatments. Graphical abstract

Alterations in CD39/CD73 axis of T cells associated with COVID‐19 severity

“…Here we described increased proportions of CD4 + CD39 + T cells and lower frequencies of CD4 + CD73 + and CD8 + CD73 + in the peripheral blood of severe COVID‐19 patients. Our results contrast, at least in part, with previous data from da Silva et al ( 2022 ) who found increased expression of both CD39 and CD73 ectonucleotidases in CD45 + leukocytes. In this sense, these results indicate that purinergic signaling may be compromised in several blood immune cells, including monocytes and neutrophils.…”

“…Recent data highlighted the increased inosine levels and upregulated adenosine deaminase activity in the blood of COVID‐19 patients, suggesting increased adenosine metabolization during active SARS‐CoV‐2 infection (Schultz et al, 2022 ). On the other hand, the hydrolysis of ATP seems to be reduced by PBMC, while platelets showed the highest nucleotide hydrolysis in severe and moderate COVID‐19 patients (da Silva et al, 2022 ). Adenosine binds the P1 receptors, mainly the AR2A subtype, of immune cells (i.e., lymphocytes, monocytes, and macrophages) to induce several events to suppress the inflammatory response, such as the downregulation of the master inflammatory transcription factor NF‐κB (Linden & Cekic, 2012 ; Mandapathil et al, 2010 ; Sitkovsky et al, 2004 ).…”

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

“…Like us, others have suggested that increased systemic levels of ATP are likely to be involved in the immunopathogenesis of COVID-19 (62,63), possibly as consequence of the altered expression of nucleotidases. Indeed, the accumulation of ATP has been shown the trigger inflammatory responses such as the activation of the inflammasome pathway (64,65).…”

Integrated multiomics analysis to infer COVID-19 biological insights

“…Meanwhile, the single omics approach reported only 1 unique acute-phase protein. In response to tissue injuries caused by the robust immune response, pro-inflammation, clot formation, and cell damage, cells consume more ATP and produce more purine derivatives like adenosine, guanosine, and inosine, which have anti-inflammatory properties 33 , 36 . In this study, purine metabolism, signaling, and transport pathways were highly enriched by the multi-omics analysis.…”