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Molecular Evolution of Transition Metal Bioavailability at the Host-Pathogen Interface.
Antelo, GT, Vila, AJ, Giedroc, DP, Capdevila, DA
Trends in microbiology. 2021;(5):441-457
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Abstract
The molecular evolution of the adaptive response at the host-pathogen interface has been frequently referred to as an 'arms race' between the host and bacterial pathogens. The innate immune system employs multiple strategies to starve microbes of metals. Pathogens, in turn, develop successful strategies to maintain access to bioavailable metal ions under conditions of extreme restriction of transition metals, or nutritional immunity. However, the processes by which evolution repurposes or re-engineers host and pathogen proteins to perform or refine new functions have been explored only recently. Here we review the molecular evolution of several human metalloproteins charged with restricting bacterial access to transition metals. These include the transition metal-chelating S100 proteins, natural resistance-associated macrophage protein-1 (NRAMP-1), transferrin, lactoferrin, and heme-binding proteins. We examine their coevolution with bacterial transition metal acquisition systems, involving siderophores and membrane-spanning metal importers, and the biological specificity of allosteric transcriptional regulatory proteins tasked with maintaining bacterial metallostasis. We also discuss the evolution of metallo-β-lactamases; this illustrates how rapid antibiotic-mediated evolution of a zinc metalloenzyme obligatorily occurs in the context of host-imposed nutritional immunity.
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Particulate metal exposures induce plasma metabolome changes in a commuter panel study.
Ladva, CN, Golan, R, Liang, D, Greenwald, R, Walker, DI, Uppal, K, Raysoni, AU, Tran, V, Yu, T, Flanders, WD, et al
PloS one. 2018;(9):e0203468
Abstract
INTRODUCTION Advances in liquid chromatography-mass spectrometry (LC-MS) have enabled high-resolution metabolomics (HRM) to emerge as a sensitive tool for measuring environmental exposures and corresponding biological response. Using measurements collected as part of a large, panel-based study of car commuters, the current analysis examines in-vehicle air pollution concentrations, targeted inflammatory biomarker levels, and metabolomic profiles to trace potential metabolic perturbations associated with on-road traffic exposures. METHODS A 60-person panel of adults participated in a crossover study, where each participant conducted a highway commute and randomized to either a side-street commute or clinic exposure session. In addition to in-vehicle exposure characterizations, participants contributed pre- and post-exposure dried blood spots for 2-hr changes in targeted proinflammatory and vascular injury biomarkers and 10-hr changes in the plasma metabolome. Samples were analyzed on a Thermo QExactive MS system in positive and negative electrospray ionization (ESI) mode. Data were processed and analyzed in R using apLCMS, xMSanalyzer, and limma. Features associated with environmental exposures or biological endpoints were identified with a linear mixed effects model and annotated through human metabolic pathway analysis in mummichog. RESULTS HRM detected 10-hr perturbations in 110 features associated with in-vehicle, particulate metal exposures (Al, Pb, and Fe) which reflect changes in arachidonic acid, leukotriene, and tryptophan metabolism. Two-hour changes in proinflammatory biomarkers hs-CRP, IL-6, IL-8, and IL-1β were also associated with 10-hr changes in the plasma metabolome, suggesting diverse amino acid, leukotriene, and antioxidant metabolism effects. A putatively identified metabolite, 20-OH-LTB4, decreased after in-vehicle exposure to particulate metals, suggesting a subclinical immune response. CONCLUSIONS Acute exposures to traffic-related air pollutants are associated with broad inflammatory response, including several traditional markers of inflammation.
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Metals in fungal virulence.
Gerwien, F, Skrahina, V, Kasper, L, Hube, B, Brunke, S
FEMS microbiology reviews. 2018;(1)
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Abstract
Metals are essential for life, and they play a central role in the struggle between infecting microbes and their hosts. In fact, an important aspect of microbial pathogenesis is the 'nutritional immunity', in which metals are actively restricted (or, in an extended definition of the term, locally enriched) by the host to hinder microbial growth and virulence. Consequently, fungi have evolved often complex regulatory networks, uptake and detoxification systems for essential metals such as iron, zinc, copper, nickel and manganese. These systems often differ fundamentally from their bacterial counterparts, but even within the fungal pathogens we can find common and unique solutions to maintain metal homeostasis. Thus, we here compare the common and species-specific mechanisms used for different metals among different fungal species-focusing on important human pathogens such as Candida albicans, Aspergillus fumigatus or Cryptococcus neoformans, but also looking at model fungi such as Saccharomyces cerevisiae or A. nidulans as well-studied examples for the underlying principles. These direct comparisons of our current knowledge reveal that we have a good understanding how model fungal pathogens take up iron or zinc, but that much is still to learn about other metals and specific adaptations of individual species-not the least to exploit this knowledge for new antifungal strategies.
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Subversion of nutritional immunity by the pathogenic Neisseriae.
Cornelissen, CN
Pathogens and disease. 2018;(1)
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Abstract
The pathogenic Neisseria species, including Neisseria meningitidis and Neisseria gonorrhoeae, are obligate human pathogens that cause significant morbidity and mortality. The success of these pathogens, with regard to causing disease in humans, is inextricably linked to their ability to acquire necessary nutrients in the hostile environment of the host. Humans deploy a significant arsenal of weaponry to defend against bacterial pathogens, not least of which are the metal-sequestering proteins that entrap and withhold transition metals, including iron, zinc and manganese, from invaders. This review will discuss the general strategies that bacteria employ to overcome these metal-sequestering attempts by the host, and then will focus on the relatively uncommon 'metal piracy' approaches utilized by the pathogenic Neisseria for this purpose. Because acquiring metals from the environment is critical to microbial survival, interfering with this process could impede growth and therefore disease initiation or progression. This review will also discuss how interfering with metal uptake by the pathogenic Neisseriae could be deployed in the development of novel or improved preventative or therapeutic measures against these important pathogens.
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Metal homeostasis in infectious disease: recent advances in bacterial metallophores and the human metal-withholding response.
Neumann, W, Gulati, A, Nolan, EM
Current opinion in chemical biology. 2017;:10-18
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Abstract
A tug-of-war between the mammalian host and bacterial pathogen for nutrients, including first-row transition metals (e.g. Mn, Fe, Zn), occurs during infection. Here we present recent advances about three metal-chelating metabolites that bacterial pathogens deploy when invading the host: staphylopine, staphyloferrin B, and enterobactin. These highlights provide new insights into the mechanisms of bacterial metal acquisition and regulation, as well as the contributions of host-defense proteins during the human innate immune response. The studies also underscore that the chemical composition of the microenvironment at an infection site can influence bacterial pathogenesis and the innate immune system.
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Essential metals at the host-pathogen interface: nutritional immunity and micronutrient assimilation by human fungal pathogens.
Crawford, A, Wilson, D
FEMS yeast research. 2015;(7)
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Abstract
The ability of pathogenic microorganisms to assimilate sufficient nutrients for growth within their hosts is a fundamental requirement for pathogenicity. However, certain trace nutrients, including iron, zinc and manganese, are actively withheld from invading pathogens in a process called nutritional immunity. Therefore, successful pathogenic species must have evolved specialized mechanisms in order to adapt to the nutritionally restrictive environment of the host and cause disease. In this review, we discuss recent advances which have been made in our understanding of fungal iron and zinc acquisition strategies and nutritional immunity against fungal infections, and explore the mechanisms of micronutrient uptake by human pathogenic fungi.
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Flavonoid-membrane interactions: involvement of flavonoid-metal complexes in raft signaling.
Tarahovsky, YS, Kim, YA, Yagolnik, EA, Muzafarov, EN
Biochimica et biophysica acta. 2014;(5):1235-46
Abstract
Flavonoids are polyphenolic compounds produced by plants and delivered to the human body through food. Although the epidemiological analyses of large human populations did not reveal a simple correlation between flavonoid consumption and health, laboratory investigations and clinical trials clearly demonstrate the effectiveness of flavonoids in the prevention of cardiovascular, carcinogenic, neurodegenerative and immune diseases, as well as other diseases. At present, the abilities of flavonoids in the regulation of cell metabolism, gene expression, and protection against oxidative stress are well-known, although certain biophysical aspects of their functioning are not yet clear. Most flavonoids are poorly soluble in water and, similar to lipophilic compounds, have a tendency to accumulate in biological membranes, particularly in lipid rafts, where they can interact with different receptors and signal transducers and influence their functioning through modulation of the lipid-phase behavior. In this study, we discuss the enhancement in the lipophilicity and antioxidative activity of flavonoids after their complexation with transient metal cations. We hypothesize that flavonoid-metal complexes are involved in the formation of molecular assemblies due to the facilitation of membrane adhesion and fusion, protein-protein and protein-membrane binding, and other processes responsible for the regulation of cell metabolism and protection against environmental hazards.
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Effects of metal-on-metal wear on the host immune system and infection in hip arthroplasty.
Hosman, AH, van der Mei, HC, Bulstra, SK, Busscher, HJ, Neut, D
Acta orthopaedica. 2010;(5):526-34
Abstract
BACKGROUND AND PURPOSE Joint replacement with metal-on-metal (MOM) bearings have gained popularity in the last decades in young and active patients. However, the possible effects of MOM wear debris and its corrosion products are still the subject of debate. Alongside the potential disadvantages such as toxicity, the influences of metal particles and metal ions on infection risk are unclear. METHODS We reviewed the available literature on the influence of degradation products of MOM bearings in total hip arthroplasties on infection risk. RESULTS Wear products were found to influence the risk of infection by hampering the immune system, by inhibiting or accelerating bacterial growth, and by a possible antibiotic resistance and heavy metal co-selection mechanism. INTERPRETATION Whether or not the combined effects of MOM wear products make MOM bearings less or more prone to infection requires investigation in the near future.
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Immunotoxicity and sensitizing capacity of metal compounds depend on speciation.
Di Gioacchino, M, Verna, N, Di Giampaolo, L, Di Claudio, F, Turi, MC, Perrone, A, Petrarca, C, Mariani-Costantini, R, Sabbioni, E, Boscolo, P
International journal of immunopathology and pharmacology. 2007;(2 Suppl 2):15-22
Abstract
Immunotoxicity of metal compounds is an issue of great importance due to the recent industrial application of metals with unknown toxicity on the immune system and the discovery of metal intermediary compounds not sufficiently studied yet. In this report we show results of our study on the immunotoxicity of the following metals: the Platinum group elements (Platinum, Palladium, Rhodium), Titanium and Arsenic. We applied functional and non functional assays and investigated both innate and adaptive immune systems, in particular, cell proliferation, cytokine production by PBMCs and O*2 production by neutrophils. We obtained the following results: only some Ti compounds (Titanocene, Ti ascorbate and Ti oxalate) show immunotoxicity. Trivalent As compounds (Sodium arsenite and tetraphenyl arsonium chloride) are more immunotoxic than the other investigated As compounds. Genotoxicity of Pt group compounds is in the following order: Pt > Rh > Pd. Immunotoxicity of Pt group compounds is in the following order: Pd > Pt > Rh. Lymphocytes and macrophages show a different reaction of neutrophils to metal toxicity. We can conclude that these studies show that metal immunotoxicity depends on speciation. In general speciation provides additional and often essential information in evaluating metal toxicity. However, there are many difficulties in applying speciation in investigating toxico-kinetic aspects to many metals, mainly due to the lack of information about the existence and significance of species and to the lack of analytical methods for measuring species in biological samples.