M. tuberculosis resides in permissive, lysosome-poor recruited macrophages during chronic infection

Abstract

Abstract M. tuberculosis (Mtb) infects lung phagocytes including alveolar macrophages (AM) and recruited/monocyte-derived macrophages (RM). However, little is known about the distinct roles of different cell subsets in Mtb persistence, and how they differ in controlling Mtb during chronic infection. Using fluorescent reporter strains and quantitation of live bacteria by cfu plating of sorted cell subsets, we found that AM are superior to RM in restricting and killing Mtb during chronic infection (4 wk PI). Subsequent bulk RNA-Seq of live-sorted cells from infected mice reveal that genes of the lysosome pathway are under-expressed in RM compared with AM. Using functional assays, we show here that RM have poorer lysosome function than AM. Specifically, AM not only have more lysosome content, more abundant lysosomal enzyme content and activities, but also have higher expression of proteins for lysosome acidification and more acidic lysosomes. Moreover, immunofluorescence data reveal that AM have more nuclear TFEB than RM. Nuclear translocation activates TFEB, which serves as a master regulator of lysosome biogenesis. We also found that TFEB overexpressing bone marrow-derived macrophages have enhanced abilities to kill virulent Mtb. Together, these results imply that TFEB may drive the difference of lysosome functions between AM and RM, leading to the difference in killing Mtb, and that Mtb takes advantage of intrinsically lysosome-poor RM for persistence.