Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells

• DOI: 10.1016/j.cmet.2024.01.008
• Publication Date: 2024-02-06T15:33:41Z
• Authors: Theresa Ramalho; Patricia A. Assis; Ogooluwa Ojelabi; Lin Tan; Brener Carvalho; Luiz Gardinassi; Osvaldo Campos; Philip L. Lorenzi; Katherine A. Fitz...; Cole Haynes; Douglas T. Golenbock; Ricardo T. Gazzin...
• Keywords: IRF3; Plasmodium chabaudi; IRF7

Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation disruption TCA cycle. Increased levels reduce mitochondrial functionality, which associates organellar nucleic acid release MODC restraint. We hypothesize dysfunctional mitochondria degraded DNA into cytosol. Once sensitized, activation IRF3 IRF7 promotes expression IFN-stimulated genes checkpoint markers. Indeed, depletion STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling CD8+ T control parasite proliferation. In summary, caused by MODCs leads suppressive effect cells, enhances parasitemia. provide evidence ACOD1 potential targets for adjunct antimalarial therapy.