Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of <i>Mycobacterium tuberculosis</i>.

Abstract

<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellular <i>Mtb</i> utilize 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 intracellular <i>Mtb</i>. Our analyses demonstrate that macrophages that cannot either import, store, or catabolize fatty acids restrict <i>Mtb</i> growth by both common and divergent antimicrobial 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 to <i>Mtb</i> replication, but increased induction of the same fails to rescue <i>Mtb</i> growth. Our work expands our understanding of how host fatty acid homeostasis impacts <i>Mtb</i> growth in the macrophage.