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Ranatunga, Medhavi, Rai, Rajeev, Richardson, Simon, Dyer, Paul, Harbige, Laurence S., Deacon, Andrew, Pecorino, Lauren and Getti, Giulia (2020) Leishmania aethiopica cell-to-cell spreading involves caspase-3, AkT and NF-κB but not PKC-δ activation and involves uptake of LAMP-1 positive bodies containing parasites. FEBS journal, 287 (9). pp. 1777-1797. ISSN 1742-4658
Development of human leishmaniasis is dependent on the ability of intracellular Leishmania parasites to spread and enter macrophages. The mechanism through which free promastigotes and amastigotes, bind and enter host macrophages has been previously investigated, however little is known about intracellular trafficking and cell-to-cell spreading. In this study, the mechanism involved in the spreading of L. aethiopica and L. mexicana was investigated. A significant increase in PS exhibition, cytochrome C release and active caspase 3 expression was detected (P<0.05) during L. aethiopica, but not L. mexicana spreading. A decrease (p<0.05) of Akt protein and BAD phosphorylation was also observed. The NF-kB signaling pathway and pro-apoptotic protein PKC-δ were downregulated while inhibition of caspase-3 activation prevented L aethiopica spreading. Overall suggesting that L. aethiopica induces host cell's apoptosis during spreading in a caspase-3-dependent manner. The trafficking of amastigotes within macrophages following cell to cell spreading differed from that of axenic parasites and involved co-localization with Lysosomal-associated membrane protein 1 (LAMP-1) within 10 minutes post-infection. Interestingly, following infection with axenic amastigotes and promastigotes, co-localization of parasites with LAMP-1 positive structures took place at 1 and 4 h respectively, suggesting that the membrane coat and LAMP-1 protein was derived from the donor cell. Collectively, these findings indicate that host cell apoptosis, demonstrated by PS exhibition, caspase 3 activation, cytochrome C release, downregulation of Akt, BAD phosphorylation, NF-kB activation; and independent of PKC-δ expression, is involved in L. aethiopica spreading. Moreover, L. aethiopica parasites associate with LAMP-rich structures when taken up by neighbouring macrophages.
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