Mycobacterium tuberculosis Dissemination Plays a Critical Role in Pathogenesis

Abstract

Mycobacterium tuberculosis is primarily a respiratory pathogen. However, 15% of infections worldwide occur at extrapulmonary sites causing additional complications for diagnosis and treatment of the disease. In addition, dissemination of M. tuberculosis out of the lungs is thought to be more than just a rare event leading to extrapulmonary tuberculosis, but rather a prerequisite step that occurs during all infections, producing secondary lesions that can become latent or productive. In this review we will cover the clinical range of extrapulmonary infections and the process of dissemination including evidence from both historical medical literature and animal experiments for dissemination and subsequent reseeding of the lungs through the lymphatic and circulatory systems. While the mechanisms of M. tuberculosis dissemination are not fully understood, we will discuss the various models that have been proposed to address how this process may occur and summarize the bacterial virulence factors that facilitate M. tuberculosis dissemination.

Keywords: Mycobacterium; dissemination; extrapulmonary; pathogenesis; tuberculosis.

Figure 1

Progression of human M. tuberculosis infections (1) Human tuberculosis infections are transmitted through the inhalation of contaminated aerosols. (2) Primary infections are established in the lungs, at a single site that develops into a primary granuloma. These initial sites of infection include involvement of the surrounding lymph nodes, forming a Ghon's complex. (3) Bacteria disseminate out of the lungs and into the lymphatic system, most likely entering the circulatory system through the entry of the thoracic duct into the subclavian vein. (4) Hematogenous reseeding of the lungs results in secondary granulomas located in the apical regions of the lungs and/or the extrapulmonary organs (5).

Figure 2

Proposed mechanisms of M. tuberculosis dissemination across the airway epithelia (A) The “trojan horse” model of dissemination where M. tuberculosis is carried across the epithelial barrier within infected macrophages. (B) M. tuberculosis is capable of directly infecting epithelial cells, which could result in bacteria translocating across the barrier through the epithelial cells or inducing cell death to cause a breach in the barrier (C) Passage across the epithelium may occur in specialized M cells which actively translocate antigens to the interstitium for presentation to antigen presenting cells (D) Alternatively, dendritic cells sampling antigens in the alveoli may traffic live mycobacteria to the lymph nodes.