Permutations of time and place in tuberculosis

Abstract

Tuberculosis remains a global health pandemic. The current depiction of the Mycobacterium tuberculosis life cycle proposes that airborne bacilli are inhaled and phagocytosed by alveolar macrophages, resulting in the formation of a granuloma that ruptures into the airways to reinitiate the infectious cycle. However, this widely proposed model overlooks the fact, established 100 years ago, that the initial site of M tuberculosis implantation is in the lower zones of the lungs, whereas infectious cavitary pulmonary disease develops at the lung apices. The immunological events at these two pulmonary locations are different--cavitation only occurs in the apices and not in the bases. Yet the current conceptual model of tuberculosis renders the immunology of these two temporally and spatially separated events identical. One key consequence is that prevention of primary childhood tuberculosis at the lung bases is regarded as adequate immunological protection, but extensive evidence shows that greater immunity could predispose to immunopathology and transmission at the lung apex. A much greater understanding of time and place in the immunopathological mechanisms underlying human tuberculosis is needed before further pre-exposure vaccination trials can be done.

Figure 1. The TB life cycle involves two distinct immunological loci

The widely depicted life cycle of Mycobacterium tuberculosis implies all events happen at a single locus. Aerosolised Mtb is inhaled, phagocytosed by alveolar macrophages, a granuloma forms which ultimately breaks down and ruptures into an airway, completing the cycle. However, this neglects the fact that the initial implantation of aerosolised Mtb is the lung bases (A, arrow indicates calcified Ghon focus), while infectious cavitary pulmonary TB occurs at the lung apices (B, arrow indicates cavity). Cavitation does not occur at the site of initial implantation, demonstrating that the immunology of these loci is different, but the current paradigm implies a single immunological process.

Figure 2. Immunological events differ between the lung base and apex

Childhood pulmonary TB causes a primary pneumonia in the lower zones of the lungs, which does not cavitate (A). In contrast, adult pulmonary TB occurs at the lung apices, and causes extensive cavitation (B).