Type I interferon controls macrophage metabolism during mycobacterial infection

Gregory Olson [1,2], Tara Murray [1], Ana Jahn [1], Dat Mai [1], Alan H. Diercks [1], Elizabeth S. Gold [1], Alan Aderem [1]

[1] Center for Global Infections Disease Research, Seattle Children’s Research Institute, Seattle WA
[2] Medical Scientist Training Program, University of Washington, Seattle WA

Conflicting reports of the immunometabolic response of macrophages to Mycobacterium tuberculosis (Mtb) prevents targeting these fundamental pathways with host-directed therapies or vaccines. We were intrigued that Mtb viability could explain much of the inconsistent data and hypothesized that dissecting the responses to live and heat killed Mtb would reveal pathways controlling metabolism upon Mtb infection. We found that live—but not heat killed—H37Rv (lineage 4 Mtb) decreases murine bone marrow derived macrophage (BMDM) glycolysis and induces mitochondrial dysfunction and stress. RNAseq analyses highlighted the induction of type I interferon (IFN) and downstream signaling only upon live Mtb infection. Strikingly, BMDM lacking the type I IFN receptor, IFNAR, fail to discriminate between live and heat killed Mtb transcriptionally and maintain functional glycolysis and mitochondrial respiration upon live Mtb infection. Importantly, BMDM metabolism after treatment with type I IFN alone mirrors that after live Mtb infection: restrained glycolysis and mitochondrial dysfunction. To confirm type I IFN being upstream of mitochondrial damage, we show that the metabolic changes upon live Mtb infection require the signaling protein STING and are recapitulated with exogenous type I IFN in STING KO BMDM. To investigate this in vivo, we sorted monocyte derived macrophages from wild type and IFNAR KO mice 15 days after Mtb aerosol challenge and observed that inflammatory macrophages from IFNAR KO mice have increased metabolic capacity compared to WT macrophages. We suggest that macrophage type I IFN signaling, rather than any direct mycobacterial virulence mechanism, controls macrophage metabolism upon Mtb infection.