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

Protocol for Developing a Mouse Model of Post Primary Pulmonary Tuberculosis after Hematogenous Spread in Native Lungs and Lung Implants DOI Creative Commons
Shivraj M. Yabaji, Suruchi Lata, Igor Gavrish

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 2, 2025

Summary This protocol describes a mouse model of post-primary pulmonary tuberculosis (PTB) that develops after hematogenous spread from the primary lesion in native lungs and subcutaneous lung implants. It demonstrates virulent Mycobacterium (Mtb) disseminates to lymphoid tissue many organs, but selectively damages lungs. approach particular vulnerability Mtb independent route infection provides robust platform for examining lung-specific mechanisms driving TB pathology. Highlights Mouse studying progression immune hosts Models site Allows investigation susceptibility using Graphical abstract

Language: Английский

Citations

2
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