Strategies for Zinc Uptake in Pseudomonas aeruginosa at the Host-Pathogen Interface

Abstract

As a structural, catalytic, and signaling component, zinc is necessary for the growth and development of plants, animals, and microorganisms. Zinc is also essential for the growth of pathogenic microorganisms and is involved in their metabolism as well as the regulation of various virulence factors. Additionally, zinc is necessary for infection and colonization of pathogenic microorganisms in the host. Upon infection in healthy organisms, the host sequesters zinc both intracellularly and extracellularly to enhance the immune response and prevent the proliferation and infection of the pathogen. Intracellularly, the host manipulates zinc levels through Zrt/Irt-like protein (ZIP)/ZnT family proteins and various zinc storage proteins. Extracellularly, members of the S100 protein family, such as calgranulin C, sequester zinc to inhibit microbial growth. In the face of these nutritional limitations, bacteria rely on an efficient zinc transport system to maintain zinc supplementation for proliferation and disruption of the host defense system to establish infection. Here, we summarize the strategies for zinc uptake in conditional pathogenic Pseudomonas aeruginosa, including known zinc uptake systems (ZnuABC, HmtA, and ZrmABCD) and the zinc uptake regulator (Zur). In addition, other potential zinc uptake pathways were analyzed. This review systematically summarizes the process of zinc uptake by P. aeruginosa to provide guidance for the development of new drug targets.

Keywords: Pseudomonas aeruginosa; Zur; nutritional immunity; zinc uptake system; zincophore.

FIGURE 1

The host limits the absorption of zinc by bacteria. Keratinocytes secrete psoriasin to sequester metals and prevent infection. In the infected tissue, neutrophils that release calprotectin and calgranulin C are recruited, which inhibits bacterial invasion by chelating Zn²⁺. In addition, host cells mobilize Zn²⁺ into or out of the cytoplasm through two tissue-specific Zn²⁺ transporters: Zrt/Irt-like protein (ZIP) and ZnT. In the cytosol, metallothioneins (MTs) bind Zn²⁺ to reserve, buffer, and chelate and enter or leave intracellular organelles and vesicles through ZnT and ZIP transporters.

FIGURE 2

Schematic representation of zinc uptake systems in Pseudomonas aeruginosa. In zinc-limited environments, the transcription regulator zinc uptake regulator (Zur) could not bind DNA as a repressor, leading to the expression of zinc uptake systems. The TonB-dependent transporters (ZnuD) located in the outer membrane allow the import of extracellular Zn²⁺ in the free form, directly into the periplasm. The periplasmic space protein ZnuA transmits it to the ZnuBC transporter complex of the inner membrane, further inside the cytoplasm. Periplasmic Zn²⁺ can also be imported into the cytoplasm via the P-type ATPase, HmtA. Pseudopaline synthesized by ZrmBC is released into the periplasmic space through the plasma membrane transporter ZrmD, then exported into the extracellular space through the MexAB-OprM efflux pump, where free Zn²⁺ ions are chelated extracellularly to form the pseudopaline-Zn²⁺ complex. The complex is then transported into the periplasmic space by the outer membrane receptor ZrmA and moved into the cell by an unknown inner membrane transporter or unloaded Zn²⁺ to complete extracellular Zn²⁺ uptake. OM, outer membrane; IM, inner membrane.