The AdcACB/AdcAII system is Essential for Zinc Homeostasis and an Important Contributor of Enterococcus faecalis Virulence

Bacterial pathogens require a variety of micronutrients for growth, including trace metals such as iron, manganese, and zinc (Zn). Despite their relative abundance in host environments, access to these metals is severely restricted during infection due to host-mediated defense mechanisms collectively known as nutritional immunity. Despite a growing appreciation of the importance of Zn in host-pathogen interactions, the mechanisms of Zn homeostasis and the significance of Zn to the pathophysiology of E. faecalis, a major pathogen of nosocomial and community-associated infections, have not been investigated. Here, we show that E. faecalis encoded an ABC-type transporter AdcACB and an orphan substrate-binding lipoprotein AdcAII that work cooperatively to maintain Zn homeostasis. Simultaneous inactivation of adcA and adcAII or the entire adcACB operon led to significant reduction in intracellular Zn under Zn-restricted conditions, heightened sensitivity to Zn-chelating agents including human calprotectin, aberrant cell morphology, and impaired fitness in serum ex vivo. Additionally, inactivation of adcACB and adcAII significantly reduced bacterial tolerance towards cell envelope-targeting antibiotics, which may be associated to altered fatty acid abundance and species. Lastly, we show that the AdcACB/AdcAII system contributes to E. faecalis virulence in an invertebrate (Galleria mellonella) infection model and in two catheter-associated mouse infection models that recapitulate many of the host conditions associated with enterococcal human infections. Collectively, this report reveals that high-affinity Zn import is essential for the pathogenesis of E. faecalis indicating that the surface-associated AdcA and AdcAII lipoproteins are potential therapeutic targets.

Iron, Copper, and Zinc Homeostasis: Physiology, Physiopathology, and Nanomediated Applications

Understanding of how the human organism functions has preoccupied researchers in medicine for a very long time. While most of the mechanisms are well understood and detailed thoroughly, medicine has yet much to discover. Iron (Fe), Copper (Cu), and Zinc (Zn) are elements on which organisms, ranging from simple bacteria all the way to complex ones such as mammals, rely on these divalent ions. Compounded by the continuously evolving biotechnologies, these ions are still relevant today. This review article aims at recapping the mechanisms involved in Fe, Cu, and Zn homeostasis. By applying the knowledge and expanding on future research areas, this article aims to shine new light of existing illness. Thanks to the expanding field of nanotechnology, genetic disorders such as hemochromatosis and thalassemia can be managed today. Nanoparticles (NPs) improve delivery of ions and confer targeting capabilities, with the potential for use in treatment and diagnosis. Iron deficiency, cancer, and sepsis are persisting major issues. While targeted delivery using Fe NPs can be used as food fortifiers, chemotherapeutic agents against cancer cells and microbes have been developed using both Fe and Cu NPs. A fast and accurate means of diagnosis is a major impacting factor on outcome of patients, especially when critically ill. Good quality imaging and bed side diagnostic tools are possible using NPs, which may positively impact outcome.

Phosphorus Starvation- and Zinc Excess-Induced Astragalus sinicus AsZIP2 Zinc Transporter Is Suppressed by Arbuscular Mycorrhizal Symbiosis

Zinc (Zn) is one of the most essential micronutrients for plant growth and metabolism, but Zn excess can impair many basic metabolic processes in plant cells. In agriculture, crops often experience low phosphate (Pi) and high Zn double nutrient stresses because of inordinate agro-industrial activities, while the dual benefit of arbuscular mycorrhizal (AM) fungi protects plants from experiencing both deficient and toxic nutrient stresses. Although crosstalk between Pi and Zn nutrients in plants have been extensively studied at the physiological level, the molecular basis of how Pi starvation triggers Zn over-accumulation in plants and how AM plants coordinately modulate the Pi and Zn nutrient homeostasis remains to be elucidated. Here, we report that a novel AsZIP2 gene, a Chinese milk vetch (Astragalus sinicus) member of the ZIP gene family, participates in the interaction between Pi and Zn nutrient homeostasis in plants. Phylogenetic analysis revealed that this AsZIP2 protein was closely related to the orthologous Medicago MtZIP2 and Arabidopsis AtZIP2 transporters. Gene expression analysis indicated that AsZIP2 was highly induced in roots by Pi starvation or Zn excess yet attenuated by arbuscular mycorrhization in a Pi-dependent manner. Subcellular localization and heterologous expression experiments further showed that AsZIP2 encoded a functional plasma membrane-localized transporter that mediated Zn uptake in yeast. Moreover, overexpression of AsZIP2 in A. sinicus resulted in the over-accumulation of Zn concentration in roots at low Pi or excessive Zn concentrations, whereas AsZIP2 silencing lines displayed an even more reduced Zn concentration than control lines under such conditions. Our results reveal that the AsZIP2 transporter functioned in Zn over-accumulation in roots during Pi starvation or high Zn supply but was repressed by AM symbiosis in a Pi-dependent manner. These findings also provide new insights into the AsZIP2 gene acting in the regulation of Zn homeostasis in mycorrhizal plants through Pi signal.

Global Analysis of the Zinc Homeostasis Network in Pseudomonas aeruginosa and Its Gene Expression Dynamics

Zinc is one of the most important trace elements for life and its deficiency, like its excess, can be fatal. In the bacterial opportunistic pathogen Pseudomonas aeruginosa, Zn homeostasis is not only required for survival, but also for virulence and antibiotic resistance. Thus, the bacterium possesses multiple Zn import/export/storage systems. In this work, we determine the expression dynamics of the entire P. aeruginosa Zn homeostasis network at both transcript and protein levels. Precisely, we followed the switch from a Zn-deficient environment, mimicking the initial immune strategy to counteract bacterial infections, to a Zn-rich environment, representing the phagocyte metal boost used to eliminate an engulfed pathogen. Thanks to the use of the NanoString technology, we timed the global silencing of Zn import systems and the orchestrated induction of Zn export systems. We show that the induction of Zn export systems is hierarchically organized as a function of their impact on Zn homeostasis. Moreover, we identify PA2807 as a novel Zn resistance component in P. aeruginosa and highlight new regulatory links among Zn-homeostasis systems. Altogether, this work unveils a sophisticated and adaptive homeostasis network, which complexity is key in determining a pathogen spread in the environment and during host-colonization.

Validation of Genes Affecting Rice Grain Zinc Content Through Candidate Gene-Based Association Analysis

Several key genes governing Zn homeostasis and grain zinc content (GZC) have been functionally characterized. However, the effects of these genes in diverse breeding populations have not been evaluated; thus, their availability in breeding is unclear. In this study, the effects of 65 genes related to rice zinc responses on GZC were evaluated using two panels of breeding lines, and the superior haplotypes were identified. One panel consisted of mega varieties from the International Rice Research Institute (IRRI), South Asia, and Southeast Asia (SEA), and the other panel is breeding lines/varieties from South China (SC). In addition, a multiparent advanced generation intercross (MAGIC) population, named as DC1, was also employed. Three analytical methods, single-locus mixed linear model (SL-MLM), multilocus random-SNP-effect mixed linear model (mrMLM), and haplotype-based association analysis (Hap-AA), were applied. OsIDEF1 (which explained 12.3% of the phenotypic variance) and OsZIFL7 (8.3–9.1%), OsZIP7 (18.9%), and OsIRT1 (17.9%) were identified by SL-MLM in SEA and SC, respectively, whereas no gene was significantly associated with GZC in DC1. In total, five (OsNRAMP6, OsYSL15, OsIRT1, OsIDEF1, and OsZIFL7, 7.70–15.39%), three (OsFRDL1, OsIRT1, and OsZIP7, 11.87–17.99%), and two (OsYSL7 and OsZIP7, 9.85–10.57%) genes were detected to be significantly associated with GZC in SEA, SC, and DC1 by mrMLM, respectively. Hap-AA indicated that Hap1-OsNRAMP5, Hap5-OsZIP4, Hap1-OsIRT1, Hap3-OsNRAMP6, Hap6-OsMTP1, and Hap6-OsYSL15 had the largest effects for GZC in SEA, whereas Hap3-OsOPT7, Hap4-OsIRT2, Hap4-OsZIP7, Hap5-OsIRT1, and Hap5-OsSAMS1 were the most significant in the SC population. Besides, superior alleles were also identified for the significant genes. The genes significantly associated with GZC and their superior haplotypes identified in different panels could be used in enhancing GZC through molecular breeding, which could further address the problem of Zn malnutrition among rice consumers.

Zinc as a Biomarker of Cardiovascular Health

The importance of zinc (Zn) for cardiovascular health continuously gains recognition. As shown earlier, compromised Zn homeostasis and prolonged inflammation are common features in various cardiovascular diseases (CVDs). Similarly, Zn biochemistry alters several vascular processes, and Zn status is an important feature of cardiovascular health. Zn deficiency contributes to the development of CVDs; thus, Zn manipulations, including Zn supplementation, are beneficial for preventing and treating numerous cardiovascular (CV) disorders. Finally, additional long-term, well-designed studies, performed in various population groups, should be pursued to further clarify significant relationships between Zn and CVDs.

Global analysis of the zinc homeostasis network in Pseudomonas aeruginosa and its gene expression dynamics

Zinc is one of the most important trace elements for life and its deficiency, like its excess, can be fatal. In the bacterial opportunistic pathogen Pseudomonas aeruginosa, Zn homeostasis is not only required for survival, but also for virulence and antibiotic resistance. Thus, the bacterium possesses multiple Zn import/export/storage systems. In this work, we determine the expression dynamics of the entire P. aeruginosa Zn homeostasis network at both transcript and protein levels. Precisely, we followed the switch from a Zn-deficient environment, mimicking the initial immune strategy to bacterial infections, to a Zn-rich environment, representing the phagocyte metal boost used to eliminate an engulfed pathogen. Thanks to the use of the NanoString technology, we timed the global silencing of Zn import systems and the orchestrated induction of Zn export systems. We show that the induction of Zn export systems is hierarchically organized as a function of their impact on Zn homeostasis. Moreover, we identify PA2807 as a novel Zn resistance component in P. aeruginosa and highlight new regulatory links among Zn-homeostasis systems. Altogether, this work unveils a sophisticated and adaptative homeostasis network, which complexity is key in determining a pathogen spread in the environment and during host-colonization.

The Evolving Role for Zinc and Zinc Transporters in Cadmium Tolerance and Urothelial Cancer

Cadmium (Cd) is an environmental toxicant with serious public health consequences due to its persistence within arable soils, and the ease with which it enters food chains and then, accumulates in human tissues to induce a broad range of adverse health effects. The present review focuses on the role of zinc (Zn), a nutritionally essential metal, to protect against the cytotoxicity and carcinogenicity of Cd in urinary bladder epithelial cells. The stress responses and defense mechanisms involving the low-molecular-weight metal binding protein, metallothionein (MT), are highlighted. The efflux and influx transporters of the ZnT and Zrt-/Irt-like protein (ZIP) gene families are discussed with respect to their putative role in retaining cellular Zn homeostasis. Among fourteen ZIP family members, ZIP8 and ZIP14 mediate Cd uptake by cells, while ZnT1 is among ten ZnT family members solely responsible for efflux of Zn (Cd), representing cellular defense against toxicity from excessively high Zn (Cd) intake. In theory, upregulation of the efflux transporter ZnT1 concomitant with the downregulation of influx transporters such as ZIP8 and ZIP14 can prevent Cd accumulation by cells, thereby increasing tolerance to Cd toxicity. To link the perturbation of Zn homeostasis, reflected by the aberrant expression of ZnT1, ZIP1, ZIP6, and ZIP10, with malignancy, tolerance to Cd toxicity acquired during Cd-induced transformation of a cell model of human urothelium, UROtsa, is discussed as a particular example.

Interaction Between Macro‐ and Micro-Nutrients in Plants

Nitrogen (N), phosphorus (P), sulfur (S), zinc (Zn), and iron (Fe) are some of the vital nutrients required for optimum growth, development, and productivity of plants. The deficiency of any of these nutrients may lead to defects in plant growth and decreased productivity. Plant responses to the deficiency of N, P, S, Fe, or Zn have been studied mainly as a separate event, and only a few reports discuss the molecular basis of biological interaction among the nutrients. Macro-nutrients like N, P, and/or S not only show the interacting pathways for each other but also affect micro-nutrient pathways. Limited reports are available on the investigation of two-by-two or multi-level nutrient interactions in plants. Such studies on the nutrient interaction pathways suggest that an MYB-like transcription factor, phosphate starvation response 1 (PHR1), acts as a master regulator of N, P, S, Fe, and Zn homeostasis. Similarly, light-responsive transcription factors were identified to be involved in modulating nutrient responses in Arabidopsis. This review focuses on the recent advances in our understanding of how plants coordinate the acquisition, transport, signaling, and interacting pathways for N, P, S, Fe, and Zn nutrition at the molecular level. Identification of the important candidate genes for interactions between N, P, S, Fe, and/or Zn metabolic pathways might be useful for the breeders to improve nutrient use efficiency and yield/quality of crop plants. Integrated studies on pathways interactions/cross-talks between macro‐ and micro-nutrients in the agronomically important crop plants would be essential for sustainable agriculture around the globe, particularly under the changing climatic conditions.

Non-glandular trichomes of sunflower is important in the absorption and translocation of foliar-applied Zn fertilizer

Trichomes are potentially important for absorption of foliar fertilizers, yet little is known in this regard despite previous study showing that the non-glandular trichromes (NGTs) of sunflower (Helianthus annuus) accumulate high concentrations of foliar-applied Zn. This study investigated how foliar-applied Zn accumulates in the NGTs and the subsequent fate of this Zn. Time resolved synchrotron-based X-ray fluorescence microscopy and transcriptional analyses were used to probe the movement of Zn in the NGTs, with the cuticle composition of the NGTs examined using confocal Raman microscopy. The accumulation of Zn in the NGTs is both an initial preferential absorption process and a subsequent translocation process. The preferred absorption is likely because the NGT base has a higher hydrophilicity. The subsequent translocation is due to the presence of plasmodesmata, Zn chelating ligands and Zn transporters in the NGTs. Furthermore, the Zn that was sequestered in the NGTs eventually translocated out once the leaf Zn concentration had decreased, suggesting that the NGTs are also important in maintaining the leaf Zn homeostasis. This study demonstrates for the first time that trichomes have a key structural and functional role in the absorption and translocation of foliar-applied Zn.