Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 17 July 2021 / Approved: 19 July 2021 / Online: 19 July 2021 (11:02:57 CEST)
Version 2 : Received: 28 September 2021 / Approved: 29 September 2021 / Online: 29 September 2021 (09:56:22 CEST)

How to cite: Brown, R.E.; Hunter, R.L. Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Hostdirected Therapies. Preprints 2021, 2021070404 (doi: 10.20944/preprints202107.0404.v1). Brown, R.E.; Hunter, R.L. Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Hostdirected Therapies. Preprints 2021, 2021070404 (doi: 10.20944/preprints202107.0404.v1).

Abstract

Research on the pathogenesis of tuberculosis in recent years has focused largely on the granulomatous stage of primary tuberculosis. However, post-primary tuberculosis that accounts for 80% of clinical disease is seldom studied because of the paucity of animal models and human tissues. The early lesion of post-primary tuberculosis is a subclinical obstructive lobular pneumonia that develops asymptomatically for months accumulating secreted mycobacterial antigens in alveolar macrophages and highly sensitized T cells before onset of clinical disease. Here we demonstrate antigen 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 a new synthesis of the pathogenesis of post-primary tuberculosis in which M. tuberculosis use its secreted antigens and cord factor to direct prolonged subclinical development of the early lesions in preparation for a sudden necrotizing reaction sufficient to produce a cavity and/or granulomas. Available evidence indicates that most successful human and animal vaccines and host directed therapies of post-primary tuberculosis target the early lesion, not granulomas. Recognition of this will facilitate design and evaluation of improved vaccines and therapies for tuberculosis.

Keywords

tuberculosis; secretory antigens; bronchiolar epithelium; alveolar pneumocytes; M2 polarization; COX-2, FAS; Pathogenesis; early lesion

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