From Phagosomes to Niches: Macrophage Biology in Tuberculosis Revisited

Mycobacterium tuberculosis thrives inside macrophages by modulating intracellular pathways and adapting to various lung environments. Here, we first describe how the bacillus alters phagosome maturation, endures intracellular pressure, and obtains essential nutrients. These mechanisms have been primarily defined in cell lines and macrophage models derived from monocytes. However, recent findings regarding macrophage biology suggest that such intracellular processes might differ depending on the origin and surrounding local environment. For this reason, we then examine how different cell origins and lung niches affect infection dynamics, focusing on alveolar and interstitial macrophages, which exhibit unique metabolic and immunological characteristics. Finally, we emphasize newly identified interstitial macrophage subsets related to nerves and blood vessels, whose functions in tuberculosis are mostly unexplored but could signify potential new research opportunities. Altogether, this review highlights that a better understanding of the ontogeny and location of a macrophage is as important as comprehending its microbicidal programs in the fight against tuberculosis, by merging intracellular cellular processes with cell origin and spatial context.