Activation of nuclear receptors correlates with tuberculosis severity and is a target for host-directed therapy

Abstract

Introduction: The immune response to Mycobacterium tuberculosis is accompanied by metabolic adaptations that fuel host immunity, but that are exploited by the pathogen to ensure persistence and growth. Activation of nuclear receptors, such as liver-X-receptors (LXR), orchestrate macrophage immunometabolic adaptations to infection and globally associate with tuberculosis (TB) protection. Methods: We interrogated available transcriptomic datasets of whole blood from TB patients or M. tuberculosis aerosol-infected mice to assess the expression of the signal by nuclear receptors (SNR) and LXR pathways and its correlation with disease severity. In vitro (macrophages) and in vivo (mouse model) M. tuberculosis infections were used for functional validation of the LXR act as a potential host-directed therapy. Results: We show that both the SNR and the LXR pathways are detected in the whole blood of TB patients and that their expression correlates with disease severity. Accordingly, the activation of the LXR pathway progressively increases in the lungs of M. tuberculosis-infected C57BL/6 and C3HeB/FeJ mice. Pharmacologic activation of LXR, specifically at the chronic stage of infection, improved infection outcomes and significantly prolonged the survival of the highly susceptible C3HeB/FeJ mice. Common to both mouse models and to in vitro macrophage infections, LXR activation enhanced bacterial control together with an increase in extracellular cholesterol levels. Discussion: We propose that progressive LXR activation is required to fine-tune host cholesterol availability during M. tuberculosis infections and restrict access to this nutrient during chronic stages of infections. Collectively, we identify the SNR/LXR pathways as potential biomarkers of TB severity and timely LXR activation as a candidate host-directed therapy.