Macrophage Mitochondrial Biogenesis and Metabolic Reprogramming Induced by Leishmania donovani Require Lipophosphoglycan and Type I Interferon Signaling.

Acevedo Ospina, Hamlet Adolfo; Guay-Vincent, Marie-Michèle et Descoteaux, Albert ORCID: https://orcid.org/0000-0002-0633-5309 (2022). Macrophage Mitochondrial Biogenesis and Metabolic Reprogramming Induced by Leishmania donovani Require Lipophosphoglycan and Type I Interferon Signaling. mBio , vol. 13 , nº 6:e02578. pp. 1-22. DOI: 10.1128/mbio.02578-22.

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Résumé

Pathogen-specific rewiring of host cell metabolism creates the metabolically adapted microenvironment required for pathogen replication. Here, we investigated the mechanisms governing the modulation of macrophage mitochondrial properties by the vacuolar pathogen Leishmania. We report that induction of oxidative phosphorylation and mitochondrial biogenesis by Leishmania donovani requires the virulence glycolipid lipophosphoglycan, which stimulates the expression of key transcriptional regulators and structural genes associated with the electron transport chain. Leishmania-induced mitochondriogenesis also requires a lipophosphoglycan-independent pathway involving type I interferon (IFN) receptor signaling. The observation that pharmacological induction of mitochondrial biogenesis enables an avirulent lipophosphoglycan-defective L. donovani mutant to survive in macrophages supports the notion that mitochondrial biogenesis contributes to the creation of a metabolically adapted environment propitious to the colonization of host cells by the parasite. This study provides novel insight into the complex mechanism by which Leishmania metacyclic promastigotes alter host cell mitochondrial biogenesis and metabolism during the colonization process. IMPORTANCE To colonize host phagocytes, Leishmania metacyclic promastigotes subvert host defense mechanisms and create a specialized intracellular niche adapted to their replication. This is accomplished through the action of virulence factors, including the surface coat glycoconjugate lipophosphoglycan. In addition, Leishmania induces proliferation of host cell mitochondria as well as metabolic reprogramming of macrophages. These metabolic alterations are crucial to the colonization process of macrophages, as they may provide metabolites required for parasite growth. In this study, we describe a new key role for lipophosphoglycan in the stimulation of oxidative phosphorylation and mitochondrial biogenesis. We also demonstrate that host cell pattern recognition receptors Toll-like receptor 4 (TLR4) and endosomal TLRs mediate these Leishmania-induced alterations of host cell mitochondrial biology, which also require type I IFN signaling. These findings provide new insight into how Leishmania creates a metabolically adapted environment favorable to their replication.

Type de document:	Article
Mots-clés libres:	IFNAR; Leishmania; lipophosphoglycan; macrophages; mitochondria
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	07 déc. 2023 21:09
Dernière modification:	22 mars 2024 13:02
URI:	https://espace.inrs.ca/id/eprint/13326

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