Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Host-Directed Therapies.

Robert E Brown,Robert L Hunter

doi:10.3390/pathogens10121572

Robert E Brown, Robert L Hunter

Open Access

https://doi.org/10.3390/pathogens10121572

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Abstract

The characteristic lesion of primary tuberculosis is the granuloma as is widely studied in human tissues and animal models. Post-primary tuberculosis is different. It develops only in human lungs and begins as a prolonged subclinical obstructive lobular pneumonia that slowly accumulates mycobacterial antigens and host lipids in alveolar macrophages with nearby highly sensitized T cells. After several months, the lesions undergo necrosis to produce a mass of caseous pneumonia large enough to fragment and be coughed out to produce a cavity or be retained as the focus of a post-primary granuloma. Bacteria grow massively on the cavity wall where they can be coughed out to infect new people. Here we extend these findings with the demonstration of secreted mycobacterial antigens, but not acid fast bacilli (AFB) of M. tuberculosis in the cytoplasm of ciliated bronchiolar epithelium and alveolar pneumocytes in association with elements of the programmed death ligand 1 (PD-L1), cyclo-oxygenase (COX)-2, and fatty acid synthase (FAS) pathways in the early lesion. This suggests that M. tuberculosis uses its secreted antigens to coordinate prolonged subclinical development of the early lesions in preparation for a necrotizing reaction sufficient to produce a cavity, post-primary granulomas, and fibrocaseous disease.

Highlights

Many investigators today believe that cavities form by erosion of caseating granulomas into bronchi
Earlier investigators conducted many autopsies and so were familiar with a whole series of tuberculous lesions that are seldom seen today. They recognized that the onset of clinical post-primary tuberculosis (PPTB) is preceded by 1–2 years of asymptomatic subclinical development of the early lesion in the lung before appearance of caseous pneumonia that is either coughed out to form cavities or is retained to become the focus of post-primary granulomas and fibrocaseous disease [2,3,4]
The early lesions are an obstructive lobular pneumonia that can be distinguished from non-specific inflammation by the presence of mycobacterial antigens in lipid-rich foamy alveolar macrophages

Summary

Introduction

Many investigators today believe that cavities form by erosion of caseating granulomas into bronchi. Cavities form by dissolution of caseous pneumonia, not by erosion of granulomas [1]. Earlier investigators conducted many autopsies and so were familiar with a whole series of tuberculous lesions that are seldom seen today. They recognized that the onset of clinical post-primary tuberculosis (PPTB) is preceded by 1–2 years of asymptomatic subclinical development of the early lesion in the lung before appearance of caseous pneumonia that is either coughed out to form cavities or is retained to become the focus of post-primary granulomas and fibrocaseous disease [2,3,4]. Since there is no medical reason to biopsy the early lesions and autopsies are infrequent, most investigators are unaware of their existence even though they remain familiar to radiologists as the “tree-in-bud” sign characteristic of developing PPTB [5]

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