Bacteria's PE11 protein blocks cell cleaning, lactate restores defense

Tuberculosis remains a global threat because Mycobacterium tuberculosis (Mtb) can survive inside human cells by disabling key immune defenses. One way the bacterium persists is by using surface proteins to alter its own cell wall and resist stresses such as acid and antibiotics. In work led by corresponding author Sangita Mukhopadhyay, researchers focused on one such protein, PE11, a cell wall-localized esterase previously linked to cell wall remodelling and stress resistance. Instead of looking only at the bacterium, the team asked how PE11 affects infected host cells. They discovered a new role for PE11: it interferes with the host cell’s self-cleaning machinery known as autophagy, and it disrupts the creation and acidification of lysosomes—cell compartments that normally break down microbes. The study connected these effects to a signaling chain involving FLCN, lactate, and the master regulator TFEB. By probing that FLCN–lactate–TFEB axis, the researchers were able to show that PE11 helps Mtb evade destruction inside cells, and that manipulating lactate levels can reverse some of that protection.

To uncover the mechanism, the team used a PE11-deficient Mtb strain and compared its behavior to bacteria that express PE11. They found that PE11 drives a FLCN-dependent depletion of intracellular lactate, and this loss of lactate destabilizes TFEB, a transcription factor that controls genes required for autophagic flux and lysosomal acidification. The result is downregulation of the genetic program that builds and acidifies lysosomes, allowing Mtb to persist inside host cells. Importantly, exogenous lactate supplementation restored TFEB stability, enhanced lysosomal acidification, and significantly reduced intracellular bacterial burden. The researchers also observed that lactate synergized with frontline anti-tubercular drugs to improve Mtb clearance, suggesting that boosting lactate levels can both reactivate cellular defenses and increase the effectiveness of existing antibiotic therapy. These results identify PE11 as a bacterial immune evasion factor that targets the FLCN–lactate–TFEB signaling axis to blunt host autophagy.

The findings point to a new host-directed approach to tuberculosis treatment. By revealing that PE11 undermines host defense through a specific biochemical pathway, the work suggests two complementary strategies: block PE11’s action or restore the host signals it suppresses. Lactate emerges as a promising candidate because supplementation recovered TFEB activity, improved lysosomal acidification, and lowered intracellular Mtb levels in the models described. Because lactate also enhanced the activity of frontline anti-tubercular drugs, it could allow lower antibiotic doses or shorten treatment, potentially reducing antibiotic-associated toxicity. Framing PE11 as a key immune evasion factor gives researchers a concrete bacterial target, while the FLCN–lactate–TFEB axis offers measurable host biomarkers to guide therapy. Translating these results into clinical use will require further work, but the study provides a clear mechanistic rationale for combining metabolic support of host autophagy with standard antibiotics to better clear persistent Mtb infections.