Study on Type 1 Interferon Signaling Pathway in Mycobacteria Infection

Abstract

Tuberculosis caused by Mycobacterium tuberculosis (MTB) is a fatal disease resulting one-third of world’s population is infected. Since activated macrophages are critical for initiating immune response against MTB, their pathway is important for expanding area of MTB treatment. Whereas MTB pathogenesis that promotes NF-kB pathway are well studied, the mechanism of type 1 IFN pathway and glycolysis which results beneficial for bacteria replication is uncertain. Therefore we investigated their respective effects and association between them in MTB infection. In this study, we examined that mRNA and cytokine levels of IFN-β and Hexokinase 3, glycolysis enzyme is significantly enhanced in mouse and human tissue infected with virulent MTB more than avirulent strains. To characterize the molecular mechanism of IFN-β pathway, bone-marrow derived macrophages from mouse were infected with virulent or avirulent MTB. Virulent MTB infection augmented production of cGAS (cytosolic DNA sensor) and downstream molecules including STING activation and phoshprylation of TBK1 and IRF3 but diminished pro-inflammatory cytokines produced by NF-kB pathway and IL-1β compared with avirulent strains. Moreover virulent MTB induced phosphorylation of IFN receptor cascade signaling molecules, Akt and mTOR which known as activator of glycolysis. Deficiency of STING showed decrease of phosphorylated Akt and mTOR but enhanced IL-1β production. In accordance with this, treatment of shRNA specific for Hexokinase 3 and IFN-β neutralization also increases IL-1β level. Collectively, our data demonstrates the distinct role of IFN-β during MTB infection and discovers a model for how MTB induces association between IFN-β and glycolysis to present detrimental role in host cells.