VAPA mediates lipid exchange between Leishmania amazonensis and host macrophages

Gdovinova-Lamy, Ilona et Descoteaux, Albert ORCID: https://orcid.org/0000-0002-0633-5309 (2025). VAPA mediates lipid exchange between Leishmania amazonensis and host macrophages PLoS Pathogens , vol. 21 , nº 3. pp. 1-23. DOI: 10.1371/journal.ppat.1012636.

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Résumé

Leishmania is a vacuolar pathogen that replicates within parasitophorous vacuoles inside host phagocytes. To promote its replication, Leishmania relies on a panoply of strategies to acquire macromolecules such as lipids from host macrophages. In this study, we have evaluated the role of VAPA, an endoplasmic reticulum-resident membrane protein involved in inter-organellar lipid transport, in macrophages infected with L. amazonensis. Following infection of bone marrow-derived macrophages with metacyclic L. amazonensis promastigotes, we observed that VAPA gradually associates with communal parasitophorous vacuoles. Knockdown of VAPA prevented the replication of L. amazonensis, which was accompanied by an impaired parasitophorous vacuole expansion. Using fluorescent ceramide, we established that VAPA is required for the transport of sphingolipids to the parasitophorous vacuoles and for its acquisition by L. amazonensis amastigotes. Proximity-ligation assays revealed that L. amazonensis hijacks VAPA by disrupting its interactions with the host cell lipid transfer proteins CERT and ORP1L. Finally, we found that VAPA is essential for the transfer of the Leishmania virulence glycolipid lipophosphoglycan from the parasitophorous vacuoles to the host cell endoplasmic reticulum. We propose that VAPA contributes to the ability of L. amazonensis to colonize macrophages by mediating bi-directional transfer of lipids essential for parasite replication and virulence between the parasitophorous vacuoles and the host cell endoplasmic reticulum. © 2025 Gdovinova, Descoteaux. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Type de document:	Article
Informations complémentaires:	Funding: This work was supported by Canadian Institutes of Health Research (www.cihr-irsc.gc.ca) grants PJT-156416 and PJT-186114 to AD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Mots-clés libres:	Leishmania; Small interfering RNA; Promastigotes; Macrophages; Parasitic diseases; Lipids; Host cells; Sphingolipids
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	07 juill. 2025 18:50
Dernière modification:	07 juill. 2025 18:50
URI:	https://espace.inrs.ca/id/eprint/16448

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