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Lipid Peroxidation and Type I Interferon Coupling Fuels Pathogenic Macrophage Activation Causing Tuberculosis Susceptibility.
Yabaji, Shivraj M; Zhernovkov, Vadim; Araveti, Prasanna Babu; Lata, Suruchi; Rukhlenko, Oleksii S; Al Abdullatif, Salam; Vanvalkenburg, Arthur; Alekseev, Yuriy; Ma, Qicheng; Dayama, Gargi; Lau, Nelson C; Johnson, W Evan; Bishai, William R; Crossland, Nicholas A; Campbell, Joshua D; Kholodenko, Boris N; Gimelbrant, Alexander A; Kobzik, Lester; Kramnik, Igor.
Afiliación
  • Yabaji SM; The National Emerging Infectious Diseases Laboratory, Boston University, Boston, MA.
  • Zhernovkov V; Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland.
  • Araveti PB; The National Emerging Infectious Diseases Laboratory, Boston University, Boston, MA.
  • Lata S; The National Emerging Infectious Diseases Laboratory, Boston University, Boston, MA.
  • Rukhlenko OS; Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland.
  • Al Abdullatif S; Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
  • Vanvalkenburg A; Rutgers University, New Jersey Medical School, Division of Infectious Disease, Department of Medicine.
  • Alekseev Y; Rutgers University, New Jersey Medical School, Center for Data Science.
  • Ma Q; The Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118.
  • Dayama G; Department of Biochemistry, and Cell Biology and Genome Science Institute, Boston University Chobanian & Avedisian School of Medicine.
  • Lau NC; Department of Biochemistry, and Cell Biology and Genome Science Institute, Boston University Chobanian & Avedisian School of Medicine.
  • Johnson WE; The National Emerging Infectious Diseases Laboratory, Boston University, Boston, MA.
  • Bishai WR; Department of Biochemistry, and Cell Biology and Genome Science Institute, Boston University Chobanian & Avedisian School of Medicine.
  • Crossland NA; Rutgers University, New Jersey Medical School, Division of Infectious Disease, Department of Medicine.
  • Campbell JD; Rutgers University, New Jersey Medical School, Center for Data Science.
  • Kholodenko BN; Center for TB Research, Johns Hopkins School of Medicine, Baltimore, Maryland.
  • Gimelbrant AA; The National Emerging Infectious Diseases Laboratory, Boston University, Boston, MA.
  • Kobzik L; The Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118.
  • Kramnik I; Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
bioRxiv ; 2024 Sep 25.
Article en En | MEDLINE | ID: mdl-38496444
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 IFNß 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos