Mycobacterium tuberculosis inhibits nuclear factor erythroid 2-related factor 2 (NRF2) activity via type 1 interferon production 4124

Abstract Description Mycobacterium tuberculosis (Mtb), the causative agent of human Tuberculosis (TB), is the leading cause of infectious death worldwide. Mtb is known to cause a T1 IFN response, which is detrimental to macrophage control of Mtb, evident by increased TB severity or reactivation of latent TB upon viral infection. However, the mechanisms underlying this are poorly understood. Mtb invades macrophages, causing the generation of excess reactive oxygen species (ROS), which can lead to programmed cell death. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor activated to combat the high levels of ROS by inducing the transcription of antioxidants (AOX). We will test the hypothesis that T1 IFNs suppress NRF2 and the AOX response. Primary macrophages from WT (C57BL6), Tpl2-/-, Ifnar1-/-, and Tpl2-/-Ifnar1-/- mice were infected with Mtb, and mRNA and protein were assayed for NRF2 and AOX. Immunoblotting for NRF2 revealed no significant differences among the genotypes with Mtb infection. Despite this, NRF2-induced AOX genes showed lower expression at the mRNA and protein levels in the T1 IFN high Tpl2-/- genotype, which was reversed by simultaneous IFNAR1 ablation. These data indicate that T1 IFN signaling suppresses NRF2-induced AOX responses, but not NRF2 itself, suggesting that T1 IFNs inhibit NRF2-dependent DNA binding or transcriptional activation. These results imply that regulation of cellular redox status could be a viable option for decreasing TB severity. Funding Sources Research supported in part by the Unversity of Georgia’s Office for the Vice President of Research, the College of Vetrinary Medicine, and the Department of Infectious Diseases Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)