Mycobacterium tuberculosis-derived linoleic acid increases regulatory T cell function to promote bacterial survival within macrophages

ABSTRACT:

Regulatory T cells (Tregs) expand during Mycobacterium tuberculosis (Mtb) infection and suppress T cell mediated control. Whether Mtb actively contributes to this process is unclear. Here, using a genome-wide mutant library, we show that expression of Mtb Rv1272c, an ATP-binding cassette transporter, increased under hypoxic condition, promotes Mtb survival in vivo by increasing lecithin import, followed by the production and release of linoleic acid. Linoleic acid released by infected macrophages promoted surface trafficking of the immune checkpoint molecule CTLA-4 in Tregs via the Ca²⁺ transporter ATP2a3. This in turn inhibited macrophage reactive oxygen species production and promoted Mtb survival inside macrophages. Rv1272c-induecd linoleic acid further promoted Mtb immune evasion via increasing CTLA-4 surface trafficking on Tregs in vivo. [AU please mention in vivo work on virulence as well] Mechanistically, linoleic acid interacts with ATP2a3 in Tregs and promotes mitochondria-associated endoplasmic reticulum (ER) membrane formation. This facilitates ER to mitochondrial Ca2+ transfer, depletion of Ca2+ in the ER, and triggers store-operated calcium entry, thus elevating cytosolic Ca2+ levels to increase Ca2+-dependent CTLA-4 surface trafficking in Tregs. These findings reveal that Mtb can use a metabolite to manipulate host responses and promote its intracellular survival.

INSTRUMENT(S): Gas Chromatography MS - - - Liquid Chromatography MS - - - Gas Chromatography MS - positive

PROVIDER: MTBLS12875 | MetaboLights | 2025-09-28

REPOSITORIES: MetaboLights