Adenosine A 2A receptor as a potential regulator of Mycobacterium leprae survival mechanisms: new insights into leprosy neural damage.

Autor: Dos Santos PMF; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Díaz Acosta CC; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.; Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, San Lorenzo, Paraguay., Rosa TLSA; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Ishiba MH; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Dias AA; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Pereira AMR; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Gutierres LD; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Pereira MP; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., da Silva Rocha M; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Rosa PS; Divisão de Pesquisa e Ensino, Instituto Lauro de Souza Lima, São Paulo, Brazil., Bertoluci DFF; Divisão de Pesquisa e Ensino, Instituto Lauro de Souza Lima, São Paulo, Brazil.; Departamento de Doenças Tropicais, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, Brazil., Meyer-Fernandes JR; Laboratório de Bioquímica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., da Mota Ramalho Costa F; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States., Marques MAM; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States., Belisle JT; Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States., Pinheiro RO; Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Rodrigues LS; Laboratório de Imunopatologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil., Pessolani MCV; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Berrêdo-Pinho M; Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Jazyk: angličtina
Zdroj: Frontiers in pharmacology [Front Pharmacol] 2024 Jun 28; Vol. 15, pp. 1399363. Date of Electronic Publication: 2024 Jun 28 (Print Publication: 2024).
DOI: 10.3389/fphar.2024.1399363
Abstrakt: Background: Leprosy is a chronic infectious disease caused by Mycobacterium leprae , which can lead to a disabling neurodegenerative condition. M. leprae preferentially infects skin macrophages and Schwann cells-glial 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-pathogen 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 2A R involved in neuroimmune response, lipid metabolism, and neuron-glia 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 M. leprae -Schwann cell interaction.
Methods: M. leprae was purified from the hind footpad of athymic nu/nu mice. ST88-14 human cells were infected with M. leprae 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. M. leprae viability was investigated by RT-qPCR, and cytokines were evaluated by enzyme-linked immunosorbent assay.
Results: We demonstrated that M. leprae -infected Schwann cells upregulated CD73 and ADA and downregulated A 2A R expression and the phosphorylation of the transcription factor CREB (p-CREB). On the other hand, activation of A 2A 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 M. leprae viability; 4) increased levels of p-CREB.
Conclusion: These findings suggest the involvement of the AdoS in leprosy neuropathogenesis and support the idea that M. leprae , by downmodulating the expression and activity of A 2A R in Schwann cells, decreases A 2A R downstream signaling, contributing to the maintenance of LD accumulation and intracellular viability of the bacillus.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 dos Santos, Díaz Acosta, Rosa, Ishiba, Dias, Pereira, Gutierres, Pereira, da Silva Rocha, Rosa, Bertoluci, Meyer-Fernandes, da Mota Ramalho Costa, Marques, Belisle, Pinheiro, Rodrigues, Pessolani and Berrêdo-Pinho.)
Databáze: MEDLINE
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