Targeting serine metabolism boosts antimycobacterial immunity during Mycobacterium tuberculosis H37Rv infection

Serine metabolism is pivotal in regulating immune cell function and molding the host microenvironment during infection, yet its impact on antimycobacterial immunity remains elusive. Here, we probe the role of serine metabolism in Mycobacterium tuberculosis (Mtb)-infected macrophages. We reveal that Mtb infection induces enzymes associated with the serine synthesis pathway (SSP) and serine transporters. Moreover, inhibition of the key SSP enzyme or restriction of exogenous serine boosts antimycobacterial immunity in both in vitro and in vivo. Depletion of serine reduces reactive oxygen species (ROS) levels by diminishing the levels of reduced nicotinamide adenine dinucleotide. This ROS reduction destabilizes hypoxia-inducible factor 1 alpha, impairing glucose uptake and adenosine triphosphate (ATP) production. Consequently, reduced ATP production activates adenosine monophosphate-activated protein kinase, which inhibits mTOR and induces autophagy, thereby exerting an antimycobacterial effect. These findings underscore serine's role as a crucial immune metabolite during Mtb infection and propose that manipulating serine metabolism holds therapeutic promise against mycobacterial infections.