Integrating Lung Physiology, Immunology, and Tuberculosis

Abstract

Lungs are directly exposed to the air, have enormous surface area, and enable gas exchange in air-breathing animals. They are constantly 'attacked' by microbes from both outside and inside and thus possess a unique, highly regulated local immune defense system which efficiently allows for microbial clearance while minimizing damaging inflammatory responses. As a prototypic host-adapted airborne pathogen, Mycobacterium tuberculosis traverses the lung and has several 'interaction points' (IPs) which it must overcome to cause infection. These interactions are critical, not only from a pathogenesis perspective but also in considering the effectiveness of therapies and vaccines in the lungs. Here we discuss emerging views on immunologic interactions occurring in the lungs for M. tuberculosis and their impact on infection and persistence.

Keywords: Mycobacterium tuberculosis; airborne infection; mucosal immunity; respiratory track; tuberculosis.

Figure 1. Key respiratory track interaction points for M. tuberculosis which must be overcome for establishment of infection

M. tuberculosis infection requires transmission of an M. tuberculosis droplet. Intrinsic and extrinsic properties of the M. tuberculosis droplet will determine its success to reach the alveolar space. In this path to infection, M. tuberculosis droplets most transit the nose and sinuses, which contain mechanical and secretory mechanisms that limit entry of large M. tuberculosis droplets to the lower respiratory track. M. tuberculosis droplets of 3–5 microns encounter the tracheobronchial tree [Interaction Point (IP) #1] where they encounter several epithelial cell types that work together in facilitating mucociliary clearance. M. tuberculosis droplets next encounter divisions of bronchi into a myriad of bronchiolar types (IP#2) which terminate in alveolar ducts made up of alveolar sacs (IP#3). Here M. tuberculosis droplets will settle onto ALF which further disperses the droplets and reshapes M. tuberculosis bacilli as they encounter resident alveolar cells. The most abundant cells in the alveolar space are AT-I and AT-II cells. However, AMs are the main resident professional phagocyte which serves as the niche for M. tuberculosis survival within the host. The M. tuberculosis-infected AM will further trigger a series of complex and poorly understood innate immune events that result in generation of the adaptive cellular immune response with formation of granulomas (IP#4) that control infection but allow for bacterial persistence and serve as a barrier to therapy.