De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis
Successful control of Mycobacterium tuberculosis (Mtb) infection by macrophages relies on immunometabolic reprogramming, where the role of fatty acids (FAs) remains poorly understood. Recent studies unraveled Mtb's capacity to acquire saturated and monounsaturated FAs via the Mce1 importer. However, upon activation macrophages produce polyunsaturated FAs (PUFAs), mammal-specific FAs mediating the generation of key immunomodulatory eicosanoids. Here, we asked whether PUFA biosynthesis is modulated in Mtb-infected macrophages and benefits host or pathogen. Quantitative lipidomics revealed that Mtb infection activates the early PUFA biosynthetic pathway for production of eicosanoids. While PUFA synthesis blockade significantly impaired the inflammatory and antimicrobial responses of infected macrophages, it had no effect on Mtb growth in vivo. Using a click-chemistry approach, we found that Mtb efficiently imports PUFAs of the w6 subset via Mce1 in axenic culture, including the eicosanoid precursor arachidonic acid (AA). Notably, Mtb preferentially internalized AA over all other FAs in infected macrophages, but AA import by intracellular Mtb was largely independent from Mce1 and correlated with elevated AA levels within macrophages. Together, these findings reveal PUFAs as novel FA substrates for Mtb. They suggest that Mtb's import of infection-induced PUFAs may counteract their stimulatory effect on anti-mycobacterial immune responses.