Rai, R;
Ranatunga, M;
Richardson, S;
Dyer, P;
Deacon, A;
Pecorino, L;
Getti, G;
(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.
The FEBS Journal
, 287
(9)
pp. 1777-1797.
10.1111/febs.15166.
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Abstract
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 Leishmania aethiopica and Leishmania mexicana was investigated. A significant increase in phosphatidylserine (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 protein kinase B (Akt) protein and BCL2‐associated agonist of cell death (BAD) phosphorylation was also observed. The nuclear factor kappa‐light‐chain enhancer of activated B cells (NF‐kB) signaling pathway and pro‐apoptotic protein protein kinase C delta (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 min postinfection. 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 were 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 neighboring macrophages.
| Type: | Article |
|---|---|
| Title: | 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 |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/febs.15166 |
| Publisher version: | https://doi.org/10.1111/febs.15166 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10087486 |
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