P040

1:I3S- instituto de Investigação e Inovação em Saúde; 2:IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal; 3: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; 4:Doctoral Program in Molecular and Cell Biology, ICBAS -Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal; 5:Global Health and Tropical Medicine, Associate Laboratory in Translation and Innovation Towards Global Health, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal; 6:INASA - Instituto Nacional de Saúde Pública da Guiné-Bissau; 7:Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau; 8:Genomics Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany; 9:Dept of Infectious Diseases, Aarhus University Hospital, Denmark; 10:GloHAU Center for Global Health, Aarhus University, Denmark

Tuberculosis (TB) continues to pose a major global health challenge, with host immune responses playing a crucial role in shaping disease outcomes. In this study, we revisit the role of the “Signalling by Nuclear Receptors” (SNR) pathway in TB by integrating whole blood transcriptomics from different cohorts of TB patients with experimental validation in preclinical models. We identified the SNR pathway as a transcriptional signature associated with TB severity across independent patient datasets. In mouse models that mirror the immune landscape of human TB, we observed a progressive, time-dependent upregulation of the SNR component liver-X-receptor (LXR) genes in both resistant (C57BL/6) and susceptible (C3HeB/FeJ) strains upon Mycobacterium tuberculosis infection. Notably, pharmacological activation of the LXR pathway during later stages of infection significantly reduced pulmonary bacterial burdens and prolonged survival of susceptible mice. This effect was accompanied by enhanced cholesterol efflux and improved macrophage-mediated control of M. tuberculosis, suggesting that LXR-driven modulation of host lipid metabolism can restrict bacterial access to a critical nutrient during chronic infection. Importantly, this antibacterial effect occurred independently of major inflammatory changes or tissue damage. Our findings position the SNR/LXR axis as a biomarker of TB severity and also as a promising target for host-directed therapy. By bridging clinical data with mechanistic insight, this study establishes the temporal activation of nuclear receptor signalling as a tractable and potentially transformative strategy to improve TB treatment.