Impaired fatty acid import or catabolism in macrophages restricts intracellular growth ofMycobacterium tuberculosis

Mycobacterium tuberculosis(Mtb) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellularMtbutilize host derived lipids to maintain infection, the role of macrophage lipid processing on the bacteria’s ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR-Cas9 genetic approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellularMtb. Our analyzes demonstrate that macrophages which cannot either import, store or catabolize fatty acids restrictMtbgrowth by both common and divergent anti-microbial mechanisms, including increased glycolysis, increased oxidative stress, production of pro-inflammatory cytokines, enhanced autophagy and nutrient limitation. We also show that impaired macrophage lipid droplet biogenesis is restrictive toMtbreplication, but increased induction of the same fails to rescueMtbgrowth. Our work expands our understanding of how host fatty acid homeostasis impactsMtbgrowth in the macrophage.