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

Ana Raquel Maceiras^1,2,3Marta Lisete Silva^1*Joana Couto⁴Rute Gonçalves^4,5Marco Silva^1,5Salvador Macedo¹Diana Machado⁶Iaia Indafa^7,8Armando Sifna^8,9Cesaltina D. Malaca^8,9Nelson I. Namara^8,9Lilica Hulile Sanca^8,9Pedro N. S. Rodrigues^1,2Miguel Viveiros¹⁰Frauke Rudolf^11,8Christian Wejse^12,8Baltazar Cá^1,2,8,9Margarida Saraiva^1,2*

• ¹Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
• ²Universidade do Porto Instituto de Biologia Molecular e Celular, Porto, Portugal
• ³Wellcome Sanger Institute, Hinxton, United Kingdom
• ⁴Universidade do Porto Instituto de Investigacao e Inovacao em Saude, Porto, Portugal
• ⁵Doctoral Program in Molecular and Cell Biology, ICBAS -Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
• ⁶Universidade Nova de Lisboa Saude Global e Medicina Tropical, Lisbon, Portugal
• ⁷INASA - Instituto Nacional de Saúde Pública da Guiné-Bissau, Guiné Bissau, Guinea-Bissau
• ⁸Bandim Health Project, Bissau, Guinea-Bissau
• ⁹INASA - Instituto Nacional de Saúde Pública da Guiné-Bissau, Guine Bissau, Guinea-Bissau
• ¹⁰Universidade Nova de Lisboa Instituto de Higiene e Medicina Tropical, Lisbon, Portugal
• ¹¹Dept of Infectious Diseases, Aarhus University Hospital, Denmark, Denmark, Denmark
• ¹²GloHAU Center for Global Health, Aarhus University, Denmark, Denmark, Denmark

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. Nuclear receptors, such as liver-X-receptors (LXR), orchestrate macrophage immunometabolic adaptations to infection and globally associate with tuberculosis (TB) protection. Here, we show that the "signalling by nuclear receptors" (SNR) pathway is detected in the whole blood of TB patients and that its expression correlates with disease severity. Accordingly, we also show that 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. 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 pathway as a potential biomarker of TB severity and timely LXR activation as a candidate host-directed therapy.