Not too fat to fight: The emerging role of macrophage fatty acid metabolism in immunity to Mycobacterium tuberculosis

Abstract

While the existence of a special relationship between Mycobacterium tuberculosis (Mtb) and host lipids has long been known, it remains a challenging enigma. It was clearly established that Mtb requires host fatty acids (FAs) and cholesterol to produce energy, build its distinctive lipid-rich cell wall, and produce lipid virulence factors. It was also observed that in infected hosts, Mtb constantly resides in a FA-rich environment that the pathogen contributes to generate by inducing a lipid-laden "foamy" phenotype in host macrophages. These observations and the proximity between lipid droplets and phagosomes containing bacteria within infected macrophages gave rise to the hypothesis that Mtb reprograms host cell lipid metabolism to ensure a continuous supply of essential nutrients and its long-term persistence in vivo. However, recent studies question this principle by indicating that in Mtb-infected macrophages, lipid droplet formation prevents bacterial acquisition of host FAs while supporting the production of FA-derived protective lipid mediators. Further, in vivo investigations reveal discrete macrophage phenotypes linking the FA metabolisms of host cell and intracellular pathogen. Notably, FA storage within lipid droplets characterizes both macrophages controlling Mtb infection and dormant intracellular Mtb. In this review, we integrate findings from immunological and microbiological studies illustrating the new concept that cytoplasmic accumulation of FAs is a metabolic adaptation of macrophages to Mtb infection, which potentiates their antimycobacterial responses and forces the intracellular pathogen to shift into fat-saving, survival mode.

De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis

“…Mtb was shown to import fluorescently labeled saturated and monounsaturated fatty acids (SFAs and MUFAs, respectively) via a dedicated protein machinery named Mce1, which is coordinated with Mce4-mediated import of cholesterol and plays an important role in Mtb lipid homeostasis ( Laval et al, 2021 ; Lee et al, 2013 ; Nazarova et al, 2017 ; Nazarova et al, 2019 ; Wilburn et al, 2018 ). In addition to SFAs and MUFAs, mammalian cells produce the additional subset of polyunsaturated fatty acids (PUFAs), whose secondary metabolites shape macrophage effector functions ( Dennis and Norris, 2015 ; Mayer-Barber and Sher, 2015 ).…”

Host Immune-Metabolic Adaptations Upon Mycobacterial Infections and Associated Co-Morbidities

“…In addition to reprogramming energetic metabolism, M.tb infection rewires the lipid metabolism of host macrophages through inhibition of catabolic pathways (lipid droplet [LD] lysis and β-oxidation of fatty acids) and concomitant activation of lipid uptake, mobilization and de novo synthesis ( 78 ). This leads M.tb -infected macrophages to acquire a foamy phenotype, due to the cytoplasmic accumulation of LDs mainly composed of triacylglycerol (TAGs), a storage form of fatty acids, and cholesteryl esters.…”

Progress of the Art of Macrophage Polarization and Different Subtypes in Mycobacterial Infection

“…First, Mφ ontology may be a major paramount factor of the inherited response in the containment of MTb infection. LDs may take part in inherent immunity against MTb by directly eliminating intracellular MTb and modulate metabolism to infection ( 54 ). Strikingly, PPAR signaling is responsible for lots of adipocyte differentiation-correlated genes, leading to amassing of intracellular lipids to accommodate M. leprae parasitization in host FCs ( 55 , 56 ).…”

“…Strikingly, PPAR signaling is responsible for lots of adipocyte differentiation-correlated genes, leading to amassing of intracellular lipids to accommodate M. leprae parasitization in host FCs ( 55 , 56 ). Furthermore, the formation of LD may support the host by averting access of MTb to host’s fatty acids (FAs) while favoring native immune responses ( 54 ). In comparison, unlike other programs, FC formation reduced the avidity of host cell and the phagocytosis of MTb while protecting the cells from death.…”