Type VII secretion system deploys an active iron uptake pathway to enhance bacterial fitness and counteract host nutritional immunity

Type VII secretion systems (T7SS) are increasingly recognized as pivotal for bacterial adaptation across both environmental and host-associated niches in Gram-positive bacteria. Although T7SS has been reported to contribute to iron acquisition, the possibility of an active, more targeted iron uptake mechanism remains underexplored. Here, we reveal a distinct, active T7SS-mediated iron import mechanism in <i>Corynebacterium glutamicum</i>. We show that T7SS expression is induced under iron limitation and oxidative stress conditions and is tightly regulated by the ferric uptake regulator (Fur) to benefit bacterial survival. Surprisingly, this iron uptake pathway relies on the T7SS-secreted effector ExsI, an iron-binding protein that collaborates with the membrane receptor ExiR to facilitate iron uptake into the cytoplasm. This ExsI-ExiR-mediated active iron acquisition mechanism enhances bacterial oxidative stress resistance and confers a competitive advantage in iron-limited environments. Furthermore, we show that ExsI homologs in <i>Mycobacterium smegmatis</i> circumvent calprotectin-mediated nutritional immunity, extending the relevance of this mechanism to host-pathogen interactions. Taken together, our data demonstrate a key role for T7SS in orchestrating active iron uptake, oxidative stress resilience, competitive fitness, and evasion of host nutritional immunity, highlighting its significant role in bacterial physiology and host-pathogen interactions.IMPORTANCEType VII secretion systems (T7SS) are increasingly recognized as an indispensable secretion system for Gram-positive bacteria, mediating processes vital for bacterial survival and pathogenesis. This work reveals a previously unrecognized mode of active iron acquisition mediated by T7SS, which not only boosts oxidative stress resistance in <i>Corynebacterium glutamicum</i> but also provides a competitive edge under nutrient-limited conditions. ExsI homologs in <i>Mycobacterium smegmatis</i> overcome calprotectin-mediated iron withholding, suggesting that T7SS-driven iron acquisition extends to immune evasion. These uncovered previously unreported functions of T7SS emphasize the indispensable importance of T7SS in bacterial physiology, enhancing our understanding of T7SS.