Extracellular ATP and Imbalance of CD4+ T Cell Compartment in Pediatric COVID-19

Abstract

Severe COVID-19 in children is rare, but the reasons underlying are unclear. Profound alterations in T cell responses have been well characterized in the course of adult severe COVID-19, but little is known about the T cell function in children with COVID-19. Here, we made three major observations in a cohort of symptomatic children with acute COVID-19: 1) a reduced frequency of circulating FoxP3+ regulatory T cells, 2) the prevalence of a TH17 polarizing microenvironment characterized by high plasma levels of IL-6, IL-23, and IL17A, and an increased frequency of CD4+ T cells expressing ROR-γt, the master regulator of TH17 development, and 3) high plasma levels of ATP together with an increased expression of the P2X7 receptor. Moreover, that plasma levels of ATP displayed an inverse correlation with the frequency of regulatory T cells but a positive correlation with the frequency of CD4+ T cells positive for the expression of ROR-γt. Collectively, our data indicate an imbalance in CD4+ T cell profiles during pediatric COVID-19 that might favor the course of inflammatory processes. This finding also suggests a possible role for the extracellular ATP in the acquisition of an inflammatory signature by the T cell compartment offering a novel understanding of the involved mechanisms.

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…Severe COVID-19 in children is rare. Compared with healthy controls, children with acute COVID-19 infections, whether severe or mild, all exhibited higher plasma levels of ATP that were negatively correlated with the frequency of regulatory T cells but positively correlated with the frequency of CD4+ T cells [ 284 ]. Conversely, the level of CD4+ T cells—regarded as a biomarker of protective immunity [ 285 ]—is usually significantly reduced in adults with severe or critical COVID-19 compared to healthy controls [ 286 ].…”

The Coming of Age of the P2X7 Receptor in Diagnostic Medicine

“…Of course, should this mechanism be operative in vivo, the obvious implication is that sufficient amounts of eATP should be present in the blood. Anecdotal reports suggest that this might be the case in COVID-19 [77,78].…”

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

“…The DAMP most frequently reported for COVID-19 is lactate dehydrogenase, a central enzyme of anaerobic glycolysis that is present in virtually all cells and that, therefore, reliably indicates cell death when occurring at high concentrations in the extracellular space ( 200 – 202 ). Other DAMPs which have been observed at elevated levels in the blood or plasma of patients with severe COVID-19 comprise high-mobility group box protein (HMGB)1 ( 51 , 110 , 111 , 202 – 206 ), S100 proteins ( 108 , 110 , 202 , 207 – 209 ), plasma hyaluronan ( 210 ), extracellular (e)ATP ( 211 , 212 ), the antimicrobial peptide LL-37 ( 213 , 214 ), histones (e.g ( 215 – 217 ), reviewed in ( 218 , 219 ) and circulating self-DNA, including nDNA ( 13 , 20 , 21 , 42 , 46 , 47 ), mtDNA ( 13 , 18 , 21 , 42 , 43 , 48 , 49 ), NET-associated cfDNA ( 201 , 215 , 220 – 222 ), histone-DNA complexes ( 219 ), and cfDNA of non-specified subcellular origin ( 45 , 48 , 50 – 54 ). As recently reviewed for sepsis ( 72 ), most of these studies reported a positive correlation of the plasma levels of at least some of the beforementioned DAMPs with the degree of disease severity (e.g., mild versus severe cases, COVID-19 patients at ICU admission versus healthy controls, ICU-admitted cases with fatal outcomes versus surviving patients, poor oxygenation status, patients with acute respiratory distress syndrome or with multisystem inflammatory syndrome in children, etc.).…”