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


Identification: Zheng-Weihao


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

Weihao Zheng, I-Chang Chang, Jason Limberis, Fei Ning, Joel D. Ernst*
Division of Experimental Medicine, University of California, San Francisco
*Correspondence: joel.ernst@ucsf.edu

M. tuberculosis (Mtb) resides in lung myeloid cells including alveolar macrophages (AM) and recruited/monocyte-derived macrophages (RM). However, little is known about the distinct roles of different lung macrophage subsets in Mtb persistence in vivo, and the underlying mechanisms by which these subsets restrict Mtb differently. Our unpublished data show that AM are superior to RM in controlling and killing Mtb during chronic infection (4 wk PI).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 underexpressed 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 lysosomal enzyme and higher lysosome activities, but also have more acidic lysosomes. Immunofluorescence analysis of sorted cells reveal that AM have more nuclear TFEB than RM. Nuclear translocation activates TFEB, which serves as a master regulator of lysosome biogenesis. This implies that TFEB may drive the difference of lysosome content and function between AM and RM, leading to the difference in killing Mtb. Ongoing experiments are testing whether knockout or knockdown of TFEB will decrease the Mtb-killing ability of macrophages, and asking if TFEB overexpression can enhance control of Mtb in vivo.

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