{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T01:44:09Z","timestamp":1781833449460,"version":"3.54.5"},"reference-count":115,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T00:00:00Z","timestamp":1719532800000},"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. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Leprosy is a chronic infectious disease caused by <jats:italic>Mycobacterium leprae<\/jats:italic>, which can lead to a disabling neurodegenerative condition. <jats:italic>M. leprae<\/jats:italic> preferentially infects skin macrophages and Schwann cells\u2013glial cells of the peripheral nervous system. The infection modifies the host cell lipid metabolism, subverting it in favor of the formation of cholesterol-rich lipid droplets (LD) that are essential for bacterial survival. Although researchers have made progress in understanding leprosy pathogenesis, many aspects of the molecular and cellular mechanisms of host\u2013pathogen interaction still require clarification. The purinergic system utilizes extracellular ATP and adenosine as critical signaling molecules and plays several roles in pathophysiological processes. Furthermore, nucleoside surface receptors such as the adenosine receptor A<jats:sub>2A<\/jats:sub>R involved in neuroimmune response, lipid metabolism, and neuron\u2013glia interaction are targets for the treatment of different diseases. Despite the importance of this system, nothing has been described about its role in leprosy, particularly adenosinergic signaling (AdoS) during <jats:italic>M. leprae<\/jats:italic>\u2013Schwann cell interaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>M. leprae<\/jats:italic> was purified from the hind footpad of athymic <jats:italic>nu\/nu<\/jats:italic> mice. ST88-14 human cells were infected with <jats:italic>M. leprae<\/jats:italic> in the presence or absence of specific agonists or antagonists of AdoS. Enzymatic activity assays, fluorescence microscopy, Western blotting, and RT-qPCR analysis were performed. <jats:italic>M. leprae<\/jats:italic> viability was investigated by RT-qPCR, and cytokines were evaluated by enzyme-linked immunosorbent assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated that <jats:italic>M. leprae<\/jats:italic>-infected Schwann cells upregulated CD73 and ADA and downregulated A<jats:sub>2A<\/jats:sub>R expression and the phosphorylation of the transcription factor CREB (p-CREB). On the other hand, activation of A<jats:sub>2A<\/jats:sub>R with its selective agonist, CGS21680, resulted in: 1) reduced lipid droplets accumulation and pro-lipogenic gene expression; 2) reduced production of IL-6 and IL-8; 3) reduced intracellular <jats:italic>M. leprae<\/jats:italic> viability; 4) increased levels of p-CREB.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest the involvement of the AdoS in leprosy neuropathogenesis and support the idea that <jats:italic>M. leprae<\/jats:italic>, by downmodulating the expression and activity of A<jats:sub>2A<\/jats:sub>R in Schwann cells, decreases A<jats:sub>2A<\/jats:sub>R downstream signaling, contributing to the maintenance of LD accumulation and intracellular viability of the bacillus.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1399363","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T04:49:26Z","timestamp":1719550166000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Adenosine A2A receptor as a potential regulator of Mycobacterium leprae survival mechanisms: new insights into leprosy neural damage"],"prefix":"10.3389","volume":"15","author":[{"given":"Plinio Marcos Freire","family":"dos Santos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chyntia Carolina","family":"D\u00edaz Acosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thabatta Leal Silveira Andrezo","family":"Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle Harumi","family":"Ishiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 Alves","family":"Dias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio Marcos Rodrigues","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u00edsa Domingos","family":"Gutierres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa Pontes","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matheus","family":"da Silva Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia Sammarco","family":"Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele F. 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