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N. gonorrhoeae (Narasimhan et al., 2022), C. jejuni (Alqurashi et al., 2021), S. Typhimurium (Eriksson et al., 1998; Cotruvo and Stubbe, 2010; Panosa et al., 2010; Cotruvo and Stubbe, 2011; Martin and Imlay, 2011), C. trachomatis (Jiang et al., 2007), A. ureae (Rose et al., 2019), S. sanguinis (Makhlynets et al., 2014), S. pneumoniae (Jayachandran et al., 2021), S. pyogenes (Roca et al., 2008), B. cereus (John et al., 2022), B. subtilis (Zhang and Stubbe, 2011), B. anthracis (Grāve et al., 2020), M. tuberculosis (Hammerstad et al., 2014). Although the RNR of C. diphtheriae has not been directly characterized, it is very likely that it is manganese-dependent, as two close non-pathogenic relatives, C. glutamicum and C. ammoniagenes, have been demonstrated to be manganese-dependent RNRs (Abbouni et al., 2009; Cox et al., 2010).
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Review
27 June 2022
Divalent Metal Uptake and the Role of ZIP8 in Host Defense Against Pathogens
Derrick R. Samuelson
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Daren L. Knoell

Manganese (Mn) and Zinc (Zn) are essential micronutrients whose concentration and location within cells are tightly regulated at the onset of infection. Two families of Zn transporters (ZIPs and ZnTs) are largely responsible for regulation of cytosolic Zn levels and to a certain extent, Mn levels, although much less is known regarding Mn. The capacity of pathogens to persevere also depends on access to micronutrients, yet a fundamental gap in knowledge remains regarding the importance of metal exchange at the host interface, often referred to as nutritional immunity. ZIP8, one of 14 ZIPs, is a pivotal importer of both Zn and Mn, yet much remains to be known. Dietary Zn deficiency is common and commonly occurring polymorphic variants of ZIP8 that decrease cellular metal uptake (Zn and Mn), are associated with increased susceptibility to infection. Strikingly, ZIP8 is the only Zn transporter that is highly induced following bacterial exposure in key immune cells involved with host defense against leading pathogens. We postulate that mobilization of Zn and Mn into key cells orchestrates the innate immune response through regulation of fundamental defense mechanisms that include phagocytosis, signal transduction, and production of soluble host defense factors including cytokines and chemokines. New evidence also suggests that host metal uptake may have long-term consequences by influencing the adaptive immune response. Given that activation of ZIP8 expression by pathogens has been shown to influence parenchymal, myeloid, and lymphoid cells, the impact applies to all mucosal surfaces and tissue compartments that are vulnerable to infection. We also predict that perturbations in metal homeostasis, either genetic- or dietary-induced, has the potential to impact bacterial communities in the host thereby adversely impacting microbiome composition. This review will focus on Zn and Mn transport via ZIP8, and how this vital metal transporter serves as a “go to” conductor of metal uptake that bolsters host defense against pathogens. We will also leverage past studies to underscore areas for future research to better understand the Zn-, Mn- and ZIP8-dependent host response to infection to foster new micronutrient-based intervention strategies to improve our ability to prevent or treat commonly occurring infectious disease.

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Review
21 June 2022
Manganese (Mn) homeostasis during streptococcal infections. During infection, neutrophils release calprotectin (CP) at infection sites (left panel). CP sequesters Mn from the invading pathogen to inhibit streptococcal growth. The intracellular Mn deficiency impairs the activity of Mn-dependent superoxide dismutases (SOD) and ribonucleotide reductases (RNR), which leads to defective antioxidant defenses against superoxide (O2−) and de novo DNA synthesis, respectively. The CP-imposed Mn deficiency is sensed by Mn-sensing metalloregulator, MtsR, and the Mn-free MtsR relieves the repression of ABC family Mn importer mtsABC. The Mn uptake during nutrient-limiting growth conditions in streptococci is mediated primarily by ABC transporters. In some streptococcal species, secondary transporters belonging to NRAMP- and ZIP-family transporters are also involved in Mn acquisition. During Mn sufficiency (middle panel), MtsR binds to Mn, interacts with promoters, and represses the expression of target genes including mtsABC. The optimal Mn levels in the cytosol promotes the activity of SOD and RNR. During Mn toxicity (right panel), the Mn efflux pump MntE detoxifies bacterial cytosol of excess Mn and promotes streptococcal survival. In the absence of MntE, high cytosolic Mn levels lead to mismetallation of peroxide sensing regulator (PerR) with Mn and results in defective antioxidant responses. Furthermore, Mn mismetallated PhpP phosphatase dephosphorylates cell division kinases StkP and MapZ, which causes improper cell division and altered bacterial cell morphologies.
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8 citations