Apoptotic induction induces<i>Leishmania aethiopica</i>and<i>L. mexicana</i>spreading in terminally differentiated THP-1 cells

Rai, Rajeev; Dyer, Paul D.R.; Richardson, Simon C. W.; Harbige, Laurence S.; Getti, Giulia

doi:10.1017/s0031182017001366

Cited by 4 publications

(15 citation statements)

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“…Although a link between Leishmania infection and apoptosis has been clearly evidenced by several reports, whether and how induction of apoptosis is linked to infection spreading in human cells remains unexplored. The recent development of an in vitro model of infection spreading in human cells allowed us to further investigate such possibility. One of the first changes that take place during apoptosis is the externalization of PS.…”

Section: Resultsmentioning

confidence: 99%

“…Spreading of parasites between cells was induced in a donor population of cells by early camptothecin treatment as previously described . Following 72‐h infection, the donor population was co‐cultured with a newly differentiated set of THP‐1 cells (recipient population).…”

Section: Resultsmentioning

confidence: 99%

“…Of the over 20 species responsible for human infection, only few have been investigated and intrinsic differences between species makes it difficult to generalize conclusions . Recent findings suggest that Leishmania amazonensis , Leishmania aethiopica, and Leishmania mexicana but not Leishmania guyanensis amastigotes induce host macrophage apoptosis . Although apoptotic induction is thought to participate in the process of parasite egress within membrane‐bound bodies rich in late endosomal markers , very little is known about the biochemical pathways involved.…”

Section: Introductionmentioning

confidence: 99%

“…The involvement of the above pathways with the process of amastigote spreading is not known and the molecular mechanisms behind apoptotic induction remain to be characterized. Interestingly, very little is also known on what happens to parasites after they have been released from their host cells, with only one study looking at the cell‐to‐cell spreading of intracellular parasites between human cells in vitro .…”

Section: Introductionmentioning

confidence: 99%

“…Very little information is available on whether this has an effect on entrance mechanisms and parasite trafficking inside the new host cells. Studies on cell‐to‐cell transfer of amastigote are limited, mostly because, until recently , an in vitro model of infection spreading between human cells has not been available.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2019

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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-lightchain enhancer of activated B cells (NF-kB) signaling pathway and pro-apoptotic protein protein kinase C delta (PKC-d) 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-d expression, is involved in L. aethiopica spreading. Moreover, L. aethiopica parasites associate with LAMP-rich structures when taken up by neighboring macrophages.Abbreviations 7AAD, 7-aminoactinomycin D; Akt, protein kinase B; BAD, BCL2-associated agonist of cell death; CF, PKC-d cleaved fragment; CL, cutaneous leishmaniasis; EEA 1, early endosome antigen 1; HI-FBS, heat-inactivated fetal bovine serum; IF1, intermediate form 1; LAMP-1, lysosomal-associated membrane protein 1; NF-kB, nuclear factor kappa-light-chain enhancer of activated B cells; PKC-d, protein kinase C delta; PMA, phorbol 12-myristate 13-acetate; PS, phosphatidylserine; RA, retinoic acid; SEM, scanning electron microscope; Ser, serine; Thr, threonine.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%