The Pathogenesis of Tuberculosis: The Early Infiltrate of Post-primary (Adult Pulmonary) Tuberculosis: A Distinct Disease Entity

Abstract

It has long been recognized that tuberculosis (TB) induces both protective and tissue damaging immune responses. This paper reviews nearly two centuries of evidence that protection and tissue damage are mediated by separate disease entities in humans. Primary TB mediates protective immunity to disseminated infection while post-primary TB causes tissue damage that results in formation of cavities. Both are necessary for continued survival of Mycobacterium tuberculosis (MTB). Primary TB has been extensively studied in humans and animals. Post-primary TB, in contrast, is seldom recognized or studied. It begins as an asymptomatic early infiltrate that may resolve or progress by bronchogenic spread to caseous pneumonia that either fragments to produce cavities or is retained to produce post-primary granulomas and fibrocaseous disease. Primary and post-primary TB differ in typical age of onset, histopathology, organ distribution, x-ray appearance, genetic predisposition, immune status of the host, clinical course and susceptibility to protection by BCG. MTB is a highly successful human parasite because it produces both primary and post-primary TB as distinct disease entities in humans. No animal reproduces this sequence of lesions. Recognition of these facts immediately suggests plausible solutions, animal models and testable hypotheses to otherwise inaccessible questions of the immunity and pathogenesis of TB.

3D microarchitecture of the human tuberculous granuloma

“…Here, we Figure S10 for high power image), providing compelling evidence for 228 expansion of necrotic lesions along the airway network to help shape granuloma structure. These 229 granulomas are surrounded by foam cells ( Figure S11), consistent with historical studies showing 230 that obstructive lobular pneumonia softens lung tissue (i.e., caseating necrosis), which is then 231 coughed up, leading to cavitation 13,32 . 232…”

Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy

“…• The pathophysiology of animal model and human lesions differ significantly (Tsai et al, 2006;Hunter, 2016Hunter, , 2018Hunter et al, 2018; Hunter and Actor, 2019) • The pros and cons of metabolic pathways generated from -omic technologies (e.g., transcriptomics, proteomics, epigenetics, and metabolomics) should be carefully considered. Generally, in eukaryotes and bacteria there is a relatively poor correlation between transcripts and corresponding protein levels (Pearson correlation coefficient of ∼0.4, Vogel and Marcotte, 2012).…”

“…It is also worth mentioning that there is great heterogeneity among lesions in terms of their spatial distribution, cellular composition, overall structure, and pathophysiology within the microenvironment of the human tuberculous lung (Lenaerts et al, 2015 ; Hunter, 2016 , 2018 ; Hunter et al, 2018 ; Pacl et al, 2018 ; Reddy et al, 2018 ; Rahman et al, 2020 ; Wells et al, 2020 ). While PET imaging can certainly capture some TB lesions, it may miss others, including hypoxic lesions.…”

Impact of COVID 19 Pandemic on Tuerculosis

“…People nearby may breathe in these bacteria and become infected. (Hunter, 2018) Unlike Covid19 TB is NOT spread by shaking hand, touching bed linens or toilet seats. Reactivation is common in Tb which has not been reported in Covid19.…”