Bacteria switch secreted proteins in response to acidic pH

Tuberculosis and related mycobacterial diseases depend on bacterial tools that manipulate host immune cells. One of those tools is the Type VII ESX secretion system, known as ESX-1, which helps bacteria deliver proteins that damage the compartments inside immune cells. A team led by Patricia A. Champion studied how ESX-1 behaves when it encounters an infection-relevant signal: acidic pH. Using an animal pathogen that also serves as a model for studying ESX-1 and tuberculosis, the researchers asked whether the set of proteins secreted by ESX-1 changes under different conditions. They found that the bacteria can switch which ESX-1 proteins they secrete in response to acidic pH, and that different groups of substrates are required in an acidic infection model. In other words, the secretion machinery does not always release the same cargo; instead, it responds to the environment, adapting its output when pH changes in ways that mimic conditions inside infected host cells.

To understand how secretion changes, the researchers compared what the bacteria released under different pH conditions and tracked the molecular signals behind those changes. They show that protein secretion mirrors shifts in substrate transcripts and in the levels of both substrate and chaperone proteins. In addition to these molecular measurements, the team leveraged two infection models to test whether the switching they observed in the lab is likely to happen during real infections. Across these approaches, the evidence supported a model of pH-responsive substrate switching: when faced with an acidic environment, ESX-1 alters which proteins are secreted, and this change is accompanied by alterations at the transcript and protein levels, including chaperones that assist secretion.

These findings reshape how we think about bacterial secretion during infection. Rather than a one-size-fits-all export system, ESX-1 appears to be flexible, choosing different protein cargos depending on environmental cues like acidic pH. The work suggests that mycobacterial pathogens may deploy distinct proteins to lyse macrophage phagosomes of different pH, tailoring their assault to the conditions encountered inside host cells. For researchers, this means studies of ESX-1 and related virulence mechanisms must consider the context of pH and other infection-relevant signals. It also provides a clearer picture of the dynamic interactions between pathogen and host during early stages of infection, with the secretion system itself actively responding to the intracellular environment.