2. Academic Validation
  3. Lipid Peroxidation and Type I Interferon Coupling Fuels Pathogenic Macrophage Activation Causing Tuberculosis Susceptibility

Lipid Peroxidation and Type I Interferon Coupling Fuels Pathogenic Macrophage Activation Causing Tuberculosis Susceptibility

  • bioRxiv. 2025 May 1:2024.03.05.583602. doi: 10.1101/2024.03.05.583602.
Shivraj M Yabaji 1,  Vadim Zhernovkov 2,  Prasanna Babu Araveti 1,  Suruchi Lata 1,  Oleksii S Rukhlenko 2,  Salam Al Abdullatif 3,  Arthur Vanvalkenburg 4 5,  Yuriy Alekseev 6,  Qicheng Ma 7,  Gargi Dayama 7,  Nelson C Lau 1 7,  W Evan Johnson 4 5,  William R Bishai 8,  Nicholas A Crossland 1 6,  Joshua D Campbell 3,  Boris N Kholodenko 2 9 10,  Alexander A Gimelbrant 11,  Lester Kobzik 12,  Igor Kramnik 1 13 14 15
Affiliations

Affiliations

  • 1 The National Emerging Infectious Diseases Laboratory, Boston University, Boston, MA.
  • 2 Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland.
  • 3 Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
  • 4 Rutgers University, New Jersey Medical School, Division of Infectious Disease, Department of Medicine.
  • 5 Rutgers University, New Jersey Medical School, Center for Data Science.
  • 6 The Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118.
  • 7 Department of Biochemistry, and Cell Biology and Genome Science Institute, Boston University Chobanian & Avedisian School of Medicine.
  • 8 Center for TB Research, Johns Hopkins School of Medicine, Baltimore, Maryland.
  • 9 Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland.
  • 10 Department of Pharmacology, Yale University School of Medicine, New Haven CT, USA.
  • 11 Altius Institute for Biomedical Sciences, Seattle, WA, USA.
  • 12 Cellecta, Inc., Mountain View, CA.
  • 13 Pulmonary Center, The Department of Medicine, Boston University Chobanian & Avedisian School of Medicine.
  • 14 Dept. of Microbiology, Boston University Chobanian & Avedisian School of Medicine.
  • 15 Lead Contact.
PMID: 38496444 DOI: 10.1101/2024.03.05.583602
Abstract

A quarter of human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop pulmonary TB. We developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: the development of necrotic lung granulomas and determined that the sst1-susceptible phenotype was driven by the aberrant macrophage activation. This study demonstrates that the aberrant response of the sst1-susceptible macrophages to prolonged stimulation with TNF is primarily driven by conflicting Myc and antioxidant response pathways leading to a coordinated failure 1) to properly sequester intracellular iron and 2) to activate Ferroptosis inhibitor Enzymes. Consequently, iron-mediated lipid peroxidation fueled Ifnβ superinduction and sustained the Type I Interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. The upregulation of Myc pathway in peripheral blood cells of human TB patients was significantly associated with poor outcomes of TB treatment. Thus, Myc dysregulation in activated macrophages results in an aberrant macrophage activation and represents a novel target for host-directed TB therapies.

Keywords

Myc; antioxidant defense; inflammation; lipid peroxidation; macrophage; tuberculosis; type I interferon.

Figures
Products