Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate Improves Host Control of Salmonella enterica Serovar Typhimurium Infection in Human Macrophages.

Autor:	van Doorn CLR; Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands., Schouten GK; Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands., van Veen S; Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands., Walburg KV; Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands., Esselink JJ; Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands., Heemskerk MT; Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands., Vrieling F; Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands., Ottenhoff THM; Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Sep 06; Vol. 12, pp. 739938. Date of Electronic Publication: 2021 Sep 06 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.739938
Abstrakt:	Global increases in the prevalence of antimicrobial resistance highlight the urgent need for novel strategies to combat infectious diseases. Recent studies suggest that host metabolic pathways play a key role in host control of intracellular bacterial pathogens. In this study we explored the potential of targeting host metabolic pathways for innovative host-directed therapy (HDT) against intracellular bacterial infections. Through gene expression profiling in human macrophages, pyruvate metabolism was identified as potential key pathway involved in Salmonella enterica serovar Typhimurium ( Stm ) infections. Next, the effect of targeting pyruvate dehydrogenase kinases (PDKs) - which are regulators of the metabolic checkpoint pyruvate dehydrogenase complex (PDC) - on macrophage function and bacterial control was studied. Chemical inhibition of PDKs by dichloroacetate (DCA) induced PDC activation and was accompanied with metabolic rewiring in classically activated macrophages (M1) but not in alternatively activated macrophages (M2), suggesting cell-type specific effects of dichloroacetate on host metabolism. Furthermore, DCA treatment had minor impact on cytokine and chemokine secretion on top of infection, but induced significant ROS production by M1 and M2. DCA markedly and rapidly reduced intracellular survival of Stm , but interestingly not Mycobacterium tuberculosis , in human macrophages in a host-directed manner. In conclusion, DCA represents a promising novel HDT compound targeting pyruvate metabolism for the treatment of Stm infections. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 van Doorn, Schouten, van Veen, Walburg, Esselink, Heemskerk, Vrieling and Ottenhoff.)
Databáze:	MEDLINE
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