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Leishmania donovani modulates host macrophage mitochondrial metabolism, integrity, and function

2020; American Association of Immunologists; Volume: 204; Issue: 1_Supplement Linguagem: Inglês

10.4049/jimmunol.204.supp.82.26

1550-6606

Hamlet Acevedo Ospina, Albert Descoteaux,

Parasites and Host Interactions

Abstract To colonize macrophages, Leishmania promastigotes employ virulence factors, including lipophosphoglycan (LPG), to impair host cell processes. Whereas previous studies revealed that Leishmania alters signaling axes that regulate mitochondrial function, scarce attention has been paid to the characterization of host cell mitochondrial metabolism during Leishmania infection and to the effectors involved therein. In this study, we addressed the hypothesis that L. donovani modulates host cell mitochondrial metabolism and function in an LPG-dependent manner. To this end, we infected bone-marrow-derived macrophages with metacyclic promastigotes and we assessed the expression kinetics of host cell nuclear and mitochondrial genes that control mitochondrial biogenesis, and we measured host mitochondrial metabolic fluxes. We found that host cell nuclear and mitochondrial genes that control mitochondrial biogenesis are upregulated in an LPG-dependent manner. We also observed that IRG-1, the enzyme that synthesizes itaconate, is highly induced during infection in an LPG-dependent manner and this response was independent of endosomal TLRs. We next found that L. donovani induces a doubling in the mtDNA/nDNA ratio in an endosomal TLRs and IFNAR-dependent manner, suggesting that L. donovani promotes host mitochondrial biogenesis in an inflammatory context. Metabolic flux analyzes showed that the OCR/ECAR ratio is modulated multiple times during infection, independently of β-oxidation, suggesing that L. donovani promastigotes induce the Warburg effect to promote energetic metabolic changes. Collectively, our data indicate that L. donovani alters host cell mitochondrial dynamics during the colonization process.