Aberrant macrophage activation and failed regeneration of pulmonary epithelium promote tuberculosis progression uniquely in lung tissue

Abstract

Pulmonary TB that develops in immunocompetent adult humans is responsible for approximately 85% of the disease burden and is central for Mtb transmission. Most humans contain Mtb infection within primary granulomatous lesions, but in certain immunocompetent humans, containment fails, leading to hematogenous spread and active pulmonary disease with the formation of necrotic lesions and cavities that enable Mtb transmission via aerosols. To reveal lung-specific microenvironments conducive for Mtb survival and replication despite systemic immunity, we use fluorescence multiplex immunohistochemistry and spatial transcriptomic analyses of heterogenous TB lesions that uniquely form in the lungs of immunocompetent but TB-susceptible B6.Sst1S mice after hematogenous spread from the primary lesion. Initially, these secondary lung lesions manifested local adoptive immunity featuring tertiary lymphoid follicles similar to resistant B6 mice and contained primarily non-replicating bacilli. Following these early events, however, the B6.Sst1S mice uniquely demonstrate expansion of myeloid cell populations with the appearance of alternatively activated macrophages, dissolution of lymphoid follicles, and the accumulation of de-differentiated lung epithelial cells. These processes led to bronchogenic expansion, broncho-occlusion, and necrosuppurative pneumonia closely resembling advanced pulmonary tuberculosis in humans. To determine whether lung parenchymal cells or lung oxygenation were necessary for the pulmonary TB progression, we implanted lung and spleen fragments subcutaneously prior to the infection. The lung implants uniquely displayed the formation of the characteristic organized granulomas with necrosis and Mtb replication that paralleled TB progression in native lungs, demonstrating that the cellular composition of inflamed lung tissue, not oxygenation, is a critical determinant of pulmonary TB progression. Our data demonstrate that deleterious bi-directional interactions of aberrantly activated macrophages with the inflammation-injured lung resident cells determine lung vulnerability to virulent Mtb in immunocompetent hosts. Because these mechanisms enable Mtb transmission among humans via aerosols, they are likely evolutionary conserved and, therefore, represent appealing targets for host-directed TB therapies.

Myc Dysregulation in Activated Macrophages Initiates Iron-Mediated Lipid Peroxidation that Fuels Type I Interferon and Compromises TB Resistance

“…As shown in Fig.6K , BCG vaccine did not offer any protection to the B6.Sst1S mice. Of note, their resistant counterparts B6, did not develop progressive TB in this model, as reported elsewhere( 26 ).…”

“…We used a mouse model of pulmonary TB where the lung lesions develop after hematogenous spread from the primary site of infection and progress exclusively in the lungs, despite systemic immunity and control of infection in other organs. Microscopic pulmonary lesions develop in the lungs of both B6 and B6.Sst1S mice, but subsequent progression occurs exclusively in the B6.Sst1S ( 26 ).…”

“…Cell growth requires labile iron that is provided by Myc via downregulation of ferritins( 51, 57 ). Recently we found that lung epithelial cells embedded within TB lesions express CSF1 a macrophage growth factor known to stimulate Myc expression ( 26 ). Thus, the CSF1 Myc axis may synergize with TNF to initiate and propagate the aberrant activation state in monocytes recruited to chronic pulmonary TB lesions.…”

“…The subcutaneous infection of mice was conducted following the procedure outlined in ( 26 ). In brief, mice were anesthetized using a ketamine-xylazine solution administered intraperitoneally.…”

“…We found a single locus on chromosome 1, sst1 ( s uper s usceptibility to t uberculosis 1), was responsible for the control of the necrotization of TB lesions ( 23 ). The sst1 -susceptible mice develop necrotic lung lesions irrespective of the route of infection – aerosol, intravenous or intradermal( 20, 21, 24–26 ) – thus demonstrating a common underlying mechanism.…”