Lipid Peroxidation and Type I Interferon Coupling Fuels Pathogenic Macrophage Activation Causing Tuberculosis Susceptibility DOI Creative Commons
Shivraj M. Yabaji, Vadim Zhernovkov, Prasanna Babu Araveti

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 10, 2024

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

Language: Английский

Aberrant macrophage activation and failed regeneration of pulmonary epithelium promote tuberculosis progression uniquely in lung tissue DOI Creative Commons
Shivraj M. Yabaji, Ming Lo, Suruchi Lata

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 20, 2023

Abstract Pulmonary tuberculosis (PTB) represents 85% of the disease burden caused by Mycobacterium (Mtb) and promotes aerosol transmission infecting about a quarter people globally. Most Mtb infections are effectively limited within primary granulomatous lesions. Containment failures lead to hematogenous spread formation post-primary destructive PTB Factors that favor survival replication in lungs after despite systemic immunity represent appealing targets for host-directed TB therapies, but currently unknown. We developed novel mouse model mimics progression chronic humans: wherein lesions form from remote lesion immunocompetent TB-susceptible B6.Sst1S mice. The mice featuring pneumonia, bronchogenic expansion broncho-occlusion closely resembling humans. Using spatial transcriptomic fluorescent multiplexed immunochemistry, we demonstrated myeloid cell populations with appearance alternatively activated macrophages, dissolution initial lymphoid follicles, accumulation de-differentiated lung epithelial cells advanced To determine whether parenchymal or oxygenation were necessary pulmonary progression, implanted spleen fragments subcutaneously serve as potential spread. (but not spleen) implants displayed characteristic organized granulomas necrosis demonstrating deleterious interactions aberrantly macrophages inflammation-injured resident cells, possibly hypoxia, oxygenation, critical determinants hosts. Necrotic also subcutaneous human tissue immune system respiratory infection. These animal models may further dissect lung-specific mechanisms host susceptibility virulent testing therapeutic interventions targeting these mechanisms.

Language: Английский

Citations

4
Lipid Peroxidation and Type I Interferon Coupling Fuels Pathogenic Macrophage Activation Causing Tuberculosis Susceptibility DOI Creative Commons
Shivraj M. Yabaji, Vadim Zhernovkov, Prasanna Babu Araveti

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 10, 2024

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

Language: Английский

Citations

0