Immunity and Immunopathology in the Tuberculous Granuloma

Abstract

Granulomas, organized aggregates of immune cells, are a defining feature of tuberculosis (TB). Granuloma formation is implicated in the pathogenesis of a variety of inflammatory disorders. However, the tuberculous granuloma has been assigned the role of a host protective structure which "walls-off" mycobacteria. Work conducted over the past decade has provided a more nuanced view of its role in pathogenesis. On the one hand, pathogenic mycobacteria accelerate and exploit granuloma formation for their expansion and dissemination by manipulating host immune responses to turn leukocyte recruitment and cell death pathways in their favor. On the other hand, granuloma macrophages can preserve granuloma integrity by exerting a microbicidal immune response, thus preventing an even more rampant expansion of infection in the extracellular milieu. Even this host-beneficial immune response required to maintain the bacteria intracellular must be tempered, as an overly vigorous immune response can also cause granuloma breakdown, thereby directly supporting bacterial growth extracellularly. This review will discuss how mycobacteria manipulate inflammatory responses to drive granuloma formation and will consider the roles of the granuloma in pathogenesis and protective immunity, drawing from clinical studies of TB in humans and from animal models--rodents, zebrafish, and nonhuman primates. A deeper understanding of TB pathogenesis and immunity in the granuloma could suggest therapeutic approaches to abrogate the host-detrimental aspects of granuloma formation to convert it into the host-beneficial structure that it has been thought to be for nearly a century.

Figure 1.

Overview of tuberculosis infection development. Host factors that are protective (green) or detrimental (red) are listed above the drawings. Note that the tumor necrosis factor (TNF) can have both beneficial and pathogenic roles. Macrophages (gray) engulf extracellular M. tuberculosis bacilli (red) in the alveolar space and transport them into deeper sites in the lung. Mycobacteria replicate within minimally microbicidal macrophages that antagonize bacterial growth via TNF-dependent mechanisms. Mycobacteria induce infected macrophage apoptosis and expression of host MMP9 in an ESX-1-dependent manner. Newly recruited macrophages engulf infected cell debris, contributing to granuloma expansion. Some of these newly infected macrophages can exit the primary granuloma and establish secondary granulomas in distal tissues. Neutrophils (light blue) can also scavenge dying infected cells and kill bacteria through an NADPH-dependent mechanism. M. tuberculosis-specific T cells (green) arrive at the granuloma and produce interferon-γ (IFN-γ) to enhance the microbicidal activity of macrophages. TNF excess and strong T-cell immunity can lead to macrophage necrosis and release of mycobacteria into the extracellular space, where they can grow relatively unchecked. Subsequent induction of MMP1 causes granuloma cavitation and release of mycobacteria into the airways.