EGFR inhibitors show mixed effects on tuberculosis in immune cells

Mycobacterium tuberculosis (Mtb) remains a leading cause of deadly, antibiotic-recalcitrant disease, and scientists are exploring ways to boost the body’s own defenses. One proposed approach is host-directed therapy (HDT), which aims to enhance immune cells so they better control intracellular pathogens like Mtb. Drug repurposing screens previously flagged epidermal growth factor receptor (EGFR) as a possible target: blocking EGFR might improve how macrophages restrict Mtb. In work led by corresponding author Bryan D. Bryson, researchers examined this idea more closely. Rather than assuming all EGFR-targeting drugs act the same, they tested multiple EGFR kinase inhibitors in human monocyte-derived macrophages to ask whether these compounds truly help macrophages control intracellular Mtb. The study set out to separate drug effects that come from changing host cell behavior from effects that act directly on the bacteria, and to characterize what kinds of bacterial stress responses emerge inside treated host cells.

At a systems level, the team found that EGFR kinase inhibitors are not generally Mtb-restrictive in human monocyte-derived macrophages. Only a few EGFR kinase inhibitors reduced intracellular Mtb, and those that did worked through heterogeneous mechanisms. Some compounds showed effects consistent with direct antibiotic activity against Mtb, while others produced host-dependent restriction that appeared likely to be EGFR-independent. During host-dependent treatments, intracellular Mtb activated defined, stress-responsive gene modules; importantly, each drug induced a unique combination of what the authors call restriction-associated stresses. The researchers then decomposed the intracellular Mtb responses into host-dependent contributions and host-independent contributions suggestive of direct drug-Mtb interaction. Those parallel lines of evidence—direct antibiotic-like activity and distinct host-mediated stresses—explain why different EGFR kinase inhibitors behaved differently in the same macrophage system.

The findings nuance the simple idea that blocking EGFR is a ready-made HDT strategy for tuberculosis. Instead of a single, predictable host benefit, EGFR kinase inhibitors can act in multiple ways: some drugs may directly impair Mtb, others may alter host processes to stress the bacteria, and some may do neither in a useful way. For drug repurposing efforts, this means it's important to test compounds from multiple angles—measuring both direct effects on the pathogen and host-mediated changes that alter bacterial stress responses. By mapping how intracellular Mtb respond to different treatments and separating host-dependent from host-independent signals, the study offers a systematic roadmap for evaluating repurposed drugs in the complex drug-host-pathogen interaction space. That careful approach can help prioritize candidates that truly enhance macrophage control of Mtb rather than relying on assumptions about a single target like EGFR.