Yersinia pseudotuberculosis secretes an Fe (II)-binding effector to evade calprotectin-mediated nutritional immunity

Abstract

Iron is an essential cofactor for core metabolic processes and is critical to both host physiology and invading pathogens. While the competition between host and pathogen for ferric iron [Fe (III)] and heme has been well characterized, microbial strategies to overcome Fe (II) limitation—particularly under calprotectin (CP)-mediated Fe (II) chelation—remain poorly understood. In this study, we show that Yersinia pseudotuberculosis (Yptb) employs its type VI secretion system 1 (T6SS1) to acquire Fe (II) through secretion of the Fe (II)-binding effector SfeP. Deletion of sfeP significantly reduced bacterial loads in wild-type mice but not in CP-deficient mice, highlighting its essential role in virulence under CP-imposed Fe (II) restriction. Mechanistically, SfeP acts as a proteinaceous ferrousophore that specifically interacts with the outer-membrane porin OmpF to facilitate Fe (II) uptake, and the resulting SfeP-mediated iron homeostasis contributes critically to bacterial resistance against oxidative and acidic stress. Together, these findings uncover a T6SS-dependent Fe (II)-scavenging pathway in which SfeP cooperates with OmpF to counteract host nutritional immunity and promote Yptb virulence. This work not only underscores the versatility of T6SS in metal acquisition and stress adaptation, but also highlights the physiological significance of CP-mediated Fe (II) sequestration in host defense against bacterial infection.

Keywords

Type VI secretion system (T6SS) / Ferrous iron transportation / Calprotectin / Nutritional immunity / OmpF / Oxidative stress / Acid stress

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Funding

National Key R&D Program of China(2021YFA0909600)

National Natural Science Foundation of China(31970114)

Shaanxi Fundamental Science Research Project for Chemistry & Biology(22JHZ008)

Special Open Fund of Key Laboratory of Experimental Marine Biology, Chinese Academy of Sciences(SKF2020NO1)

Marine Economic Development Special Fund of Fujian Province(FJHJF-L-2020-2)

project of University-Industry Cooperation from Fujian Provincial Department of Science and Technology(2020Y4007)

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