Listeria monocytogenes infection rewires host metabolism with regulatory input from type I interferons

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Müller, Mathias; Dolezal, Marlies; Lassnig, Caroline; Prchal-Murphy, Michaela; Sexl, Veronika

Abstrakt

Listeria monocytogenes (L. monocytogenes) is a food-borne bacterial pathogen. Innate immunity to L. monocytogenes is profoundly affected by type I interferons (IFN-I). Here we investigated host metabolism in L. monocytogenes-infected mice and its potential control by IFN-I. Accordingly, we used animals lacking either the IFN-I receptor (IFNAR) or IRF9, a subunit of ISGF3, the master regulator of IFN-I-induced genes. Transcriptomes and metabolite profiles showed that L. monocytogenes infection induces metabolic rewiring of the liver. This affects various metabolic pathways including fatty acid (FA) metabolism and oxidative phosphorylation and is partially dependent on IFN-I signaling. Livers and macrophages from Ifnar1(-/-) mice employ increased glutaminolysis in an IRF9-independent manner, possibly to readjust TCA metabolite levels due to reduced FA oxidation. Moreover, FA oxidation inhibition provides protection from L. monocytogenes infection, explaining part of the protection of Irf9(-/-) and Ifnar1(-/-) mice. Our findings define a role of IFN-I in metabolic regulation during L. monocytogenes infection. Metabolic differences between Irf9(-/-) and Ifnar1(-/-) mice may underlie the different susceptibility of these mice against lethal infection with L. monocytogenes. Author summary Many immune cells undergo metabolic remodeling following encounters with cytokines or pathogenic insults. This is essential to perform their downstream effector functions and eradicate the infectious agents. Drug-mediated interference with metabolic remodeling can have a strong impact on clearance of the pathogen. Here we describe metabolic changes occurring during Listeria monocytogenes (L. monocytogenes) infection of murine hosts. Infected animals show profound changes of liver metabolism that include increased glycolysis, alterations in TCA cycle metabolites and the ratio of free versus conjugated fatty acids. Similar to what has been described during viral infections, type I interferons (IFN-I), a family of cytokines produced during L. monocytogenes infections, are involved in the import of fatty acids (FA) into the mitochondria to generate energy via oxidative phosphorylation. Accordingly, in the absence of IFN-I signals, the cells oxidize less FAs and this might help the cells better fight the infection. We also speculate that infected cells instead boost glutamine utilization to supply their energy need. Our work describes metabolic rewiring that takes place during L. monocytogenes infection and the contribution of IFN-I signaling. Our study improves the understanding of listeriosis and has the potential to help us discover new drug targets against L. monocytogenes and viruses that induce IFN-I response.

Dokumententyp

Originalarbeit

Open Access Type

Gold

DOI

10.1371/journal.ppat.1009697

PubMed ID

MEDLINE:34237114