Figure 2. Mn and Zn homeostasis at the pathogen-host interface.

a. Zn²⁺ and Mn²⁺ sequestration by S100 family proteins at epithelial surfaces and within tissue abscesses. S100A7 is released at epithelial surfaces, where it inhibits bacterial invasion through chelation of Zn²⁺. In deep tissues, infection leads to recruitment of neutrophils, which deliver calprotectin (S100A8/A9) to the infection site. Calprotectin inhibits bacterial growth through chelation of Mn²⁺ and Zn²⁺ and is thought to be transported away from the abscess by an as-yet-unknown mechanism. Engulfment of bacteria by macrophages leads to decreased Zn²⁺ uptake and increased Zn²⁺ efflux from the cytoplasm and efflux of Mn²⁺ and Fe from the phagosome by NRAMP1. b. Representative Mn²⁺ and Zn²⁺ uptake systems expressed by pathogenic bacteria. c. Proposed mechanisms of Zn²⁺ intoxication employed by the host and Zn²⁺ detoxification systems expressed by pathogens. Upon infection, Zn accumulates in the phagolysosome where it is toxic to bacteria. Gram-negative and Gram-positive bacteria primarily alleviate Zn toxicity through efflux of excess Zn from the cytoplasm. d. Proposed mechanism for Zn toxicity in bacteria. When the extracellular Zn²⁺: Mn²⁺ ratio is high, Zn²⁺ binds the SBP of Mn²⁺-specific transporters, preventing Mn²⁺ binding and uptake.