{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T04:38:29Z","timestamp":1793335109210,"version":"4.5.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Despite long-term sequelae of COVID-19 are emerging as a substantial public health concern, the mechanism underlying these processes still unclear. Evidence demonstrates that SARS-CoV-2 Spike protein can reach different brain regions, irrespective of viral brain replication resulting in activation of pattern recognition receptors (PRRs) and neuroinflammation. Considering that microglia dysfunction, which is regulated by a whole array of purinergic receptors, may be a central event in COVID-19 neuropathology, we investigated the impact of SARS-CoV-2 Spike protein on microglial purinergic signaling. Here, we demonstrate that cultured microglial cells (BV2 line) exposed to Spike protein induce ATP secretion and upregulation of P2Y<jats:sub>6<\/jats:sub>, P2Y<jats:sub>12<\/jats:sub>, NTPDase2 and NTPDase3 transcripts. Also, immunocytochemistry analysis shows that spike protein increases the expression of P2X7, P2Y<jats:sub>1<\/jats:sub>, P2Y<jats:sub>6<\/jats:sub>, and P2Y<jats:sub>12<\/jats:sub> in BV2 cells. Additional, hippocampal tissue of Spike infused animals (6,5ug\/site, i.c.v.) presents increased mRNA levels of P2X7, P2Y<jats:sub>1<\/jats:sub>, P2Y<jats:sub>6<\/jats:sub>, P2Y<jats:sub>12<\/jats:sub>, NTPDase1, and NTPDase2. Immunohistochemistry experiments confirmed high expression of the P2X7 receptor in microglial cells in CA3\/DG hippocampal regions after spike infusion. These findings suggest that SARS-CoV-2 Spike protein modulates microglial purinergic signaling and opens new avenues for investigating the potential of purinergic receptors to mitigate COVID-19 consequences.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1158460","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T04:51:21Z","timestamp":1681188681000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["SARS-CoV-2 Spike protein alters microglial purinergic signaling"],"prefix":"10.3389","volume":"14","author":[{"given":"Vin\u00edcius Santos","family":"Alves","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie Alexia Cristina 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