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Two billion people are latently infected with  Mycobacterium tuberculosis  ( Mtb ).  Mtb -infected macrophages are likely to be sequestered inside the hypoxic environments of the granuloma and differentiate into lipid-loaded macrophages that contain triacylglycerol (TAG)-filled lipid droplets which may provide a fatty acid-rich host environment for  Mtb . We report here that human peripheral blood monocyte-derived macrophages and THP-1 derived macrophages incubated under hypoxia accumulate Oil Red O-staining lipid droplets containing TAG. Inside such hypoxic, lipid-loaded macrophages, nearly half the  Mtb  population developed phenotypic tolerance to isoniazid, lost acid-fast staining and accumulated intracellular lipid droplets. Dual-isotope labeling of macrophage TAG revealed that  Mtb  inside the lipid-loaded macrophages imports fatty acids derived from host TAG and incorporates them intact into  Mtb  TAG. The fatty acid composition of host and  Mtb  TAG were nearly identical suggesting that  Mtb  utilizes host TAG to accumulate intracellular TAG. Utilization of host TAG by  Mtb  for lipid droplet synthesis was confirmed when fluorescent fatty acid-labeled host TAG was utilized to accumulate fluorescent lipid droplets inside the pathogen. Deletion of the  Mtb triacylglycerol synthase 1  ( tgs1 ) gene resulted in a drastic decrease but not a complete loss in both radiolabeled and fluorescent TAG accumulation by  Mtb  suggesting that the TAG that accumulates within  Mtb  is generated mainly by the incorporation of fatty acids released from host TAG. We show direct evidence for the utilization of the fatty acids from host TAG for lipid metabolism inside  Mtb . Taqman real-time PCR measurements revealed that the mycobacterial genes  dosR ,  hspX, icl1, tgs1  and  lipY  were up-regulated in  Mtb  within hypoxic lipid loaded macrophages along with other  Mtb  genes known to be associated with dormancy and lipid metabolism.

Mycobacterium tuberculosis Uses Host Triacylglycerol to Accumulate Lipid Droplets and Acquires a Dormancy-Like Phenotype in Lipid-Loaded Macrophages