Macrophages in tuberculosis: friend or foe

Abstract

Tuberculosis (TB) remains one of the greatest threats to human health. The causative bacterium, Mycobacterium tuberculosis (Mtb) is acquired by the respiratory route. It is exquisitely human-adapted and a prototypic intracellular pathogen of macrophages, with alveolar macrophages (AMs) being the primary conduit of infection and disease. The outcome of primary infection is most often a latently infected healthy human host, in whom the bacteria are held in check by the host immune response. Such individuals can develop active TB later in life with impairment in the immune system. In contrast, in a minority of infected individuals, the host immune response fails to control the growth of bacilli, and progressive granulomatous disease develops, facilitating spread of the bacilli via infectious aerosols coughed out into the environment and inhaled by new hosts. The molecular details of the Mtb-macrophage interaction continue to be elucidated. However, it is clear that a number of complex processes are involved at the different stages of infection that may benefit either the bacterium or the host. Macrophages demonstrate tremendous phenotypic heterogeneity and functional plasticity which, depending on the site and stage of infection, facilitate the diverse outcomes. Moreover, host responses vary depending on the specific characteristics of the infecting Mtb strain. In this chapter, we describe a contemporary view of the behavior of AMs and their interaction with various Mtb strains in generating unique immunologic lung specific responses.

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

“…Although nearly onethird of the human population is infected with M. tuberculosis, only ∼10% of the infected individuals develop active disease during their lifetime. The pathogenesis of M. tuberculosis is largely because it can escape host immune defense system and thus survive within the hostile environment of human macrophages (2,3). The prolonged coevolution of M. tuberculosis with its hosts has led to multiple survival strategies to interfere with a wide range of host cellular processes, such as production of cytokines, phagolysosome biogenesis, and modulation of macrophage survival (3)(4)(5)(6).…”

Keratinocyte Growth Factor Administration Attenuates Murine Pulmonary Mycobacterium tuberculosis Infection through Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF)-dependent Macrophage Activation and Phagolysosome Fusion

“…Strains resistant to all major anti-TB drugs have emerged, and novel approaches to therapy are needed. Inhaled M. tuberculosis bacteria impact the airway epithelial lining layer and are internalized into the phagosomes of alveolar macrophages (AMs) (2)(3)(4). Infected AMs secrete TNF␣ and chemokines that coordinate the recruitment of T lymphocytes into lung granulomas, which function to contain the infected cells and to facilitate the execution of microbicidal programs (5).…”

“…Fusion of the macrophage phagosome with lysosomes is a tightly regulated event that exposes the bacterium to the acidic pH and digestive enzyme milieu within the lysosome and thereby promotes bacterial killing. M. tuberculosis can subvert host innate immune responses and survive within macrophages through a variety of adaptive mechanisms, including inhibition of phagolysosome fusion or acidification of the phagosome and scavenging of iron, leading to latency or progressive pulmonary infection (4). For the billions of individuals with latent TB, recrudescence years after the primary exposure is the most common source of new infections in the more than 9 million patients with active TB worldwide (1,7).…”

Effect of Apoptotic Cell Recognition on Macrophage Polarization and Mycobacterial Persistence

“…Their physiology can be markedly altered by both innate and adaptive immune responses (1)(2)(3)(4)(5)(6)(7)(8). Proinflammatory (M1) and anti-inflammatory (M2) macrophage polarization contributes to the resolution of inflammatory processes.…”