期刊
JOURNAL OF CELL SCIENCE
卷 133, 期 7, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.239939
关键词
ATP; Ectonucleotidase; Adenosine receptor; Leishmania donovani; Macrophage
类别
资金
- Department of Biotechnology, Ministry of Science and Technology [BT/HRD/NBA/38/03/2018]
- Indo Israel Grant
- University Grants Commission [6-10/2016(IC)]
- Department of Science and Technology [SB/SO/BB-0055/2013]
- Department of Biotechnology [221/BT(Estt)/RD-40/2014]
- University with Potential for Excellence II [UGC/148/UPE/ST1]
- University Grants Commission (New Delhi)
Intracellular survival of Leishmania donovani demands rapid production of host ATP for its sustenance. However, a gradual decrease in intracellular ATP in spite of increased glycolysis suggests ATP efflux during infection. Accordingly, upon infection, we show here that ATP is exported and the major exporter was pannexin-1, leading to raised extracellular ATP levels. Extracellular ATP shows a gradual decrease after the initial increase, and analysis of cell surface ATP-degrading enzymes revealed induction of the ectonucleotidases CD39 and CD73. Ectonucleotidase-mediated ATP degradation leads to increased extracellular adenosine (eADO), and inhibition of CD39 and CD73 in infected cells decreased adenosine concentration and parasite survival, documenting the importance of adenosine in infection. Inhibiting adenosine uptake by cells did not affect parasite survival, suggesting that eADO exerts its effect through receptor-mediated signalling. We also show that Leishmania induces the expression of adenosine receptors A(2A)R and A(2B)R, both of which are important for anti-inflammatory responses. Treating infected BALB/c mice with CD39 and CD73 inhibitors resulted in decreased parasite burden and increased host-favourable cytokine production. Collectively, these observations indicate that infection-induced ATP is exported, and after conversion into adenosine, propagates infection via receptor-mediated signalling.
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