Alveolar Macrophages Provide an Early Mycobacterium tuberculosis Niche and Initiate Dissemination

Abstract

Mycobacterium tuberculosis (Mtb) infection is initiated in the distal airways, but the bacteria ultimately disseminate to the lung interstitium. Although various cell types, including alveolar macrophages (AM), neutrophils, and permissive monocytes, are known to be infected with Mtb, the initially infected cells as well as those that mediate dissemination from the alveoli to the lung interstitium are unknown. In this study, using a murine infection model, we reveal that early, productive Mtb infection occurs almost exclusively within airway-resident AM. Thereafter Mtb-infected, but not uninfected, AM localize to the lung interstitium through mechanisms requiring an intact Mtb ESX-1 secretion system. Relocalization of infected AM precedes Mtb uptake by recruited monocyte-derived macrophages and neutrophils. This dissemination process is driven by non-hematopoietic host MyD88/interleukin-1 receptor inflammasome signaling. Thus, interleukin-1-mediated crosstalk between Mtb-infected AM and non-hematopoietic cells promotes pulmonary Mtb infection by enabling infected cells to disseminate from the alveoli to the lung interstitium.

Macrophage heterogeneity and plasticity in tuberculosis

“… A simplified model of various innate cells of macrophage origin participating during M. tuberculosis infection . In their naive stage, alveolar macrophages (AMs) that phagocytose the inhaled bacilli at alveoli exhibit an M2‐like phenotype that is more permissive for the growth of M. tuberculosis . With IFN‐γ‐mediated priming through T cells, AMs could also exhibit the M1‐like phenotype at the early stage of infection and restrict bacterial growth .…”

“…In their naive stage, alveolar macrophages (AMs) that phagocytose the inhaled bacilli at alveoli exhibit an M2-like phenotype that is more permissive for the growth of M. tuberculosis. 42 With IFN--mediated priming through T cells, AMs could also exhibit the M1-like phenotype at the early stage of infection and restrict bacterial growth. 19 However, AMs eventually acquire an M2-like phenotype after inflammation progresses.…”

Unraveling the host's immune response to infection: Seeing is believing

“…The movement of cells between compartments is necessary for the clearance of certain pathogens, yet has also been shown to promote dissemination. For instance, a non‐IVM study recently reported that the movement of infected alveolar macrophages into the interstitium may drive the dissemination of Mycobacterium tuberculosis . Although an interesting hypothesis, IVM will be necessary to track the migration of these cells to demonstrate categorically that it is indeed the alveolar macrophages that migrate into the interstitium.…”

“…For instance, a non-IVM study recently reported that the movement of infected alveolar macrophages into the interstitium may drive the dissemination of Mycobacterium tuberculosis. 72 Although an interesting hypothesis, IVM will be necessary to track the migration of these cells to demonstrate categorically that it is indeed the alveolar macrophages that migrate into the interstitium. IVM imaging of live events such as this will help to improve our understanding of the dynamic host-pathogen interactions that take place during infection with different types of intracellular and extracellular bacteria.…”

Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis

“…Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), latently infects roughly one-third of the world's population and causes 1-2 million deaths per year. The current paradigm of acute infection is that after an actively infected person aerosolizes infectious Mtb-containing particles, a naive individual inhales the bacteria that then traverse the respiratory tree to ultimately be phagocytosed by alveolar macrophages (Churchyard et al, 2017;Cohen et al, 2018). While this model can account for pulmonary TB, it is insufficient to explain some extrapulmonary forms of TB initiated by oropharyngeal infection and lacking evidence of concurrent pulmonary disease.…”