Review Article Strategies of Intracellular Pathogens for...

Review ArticleStrategies of Intracellular Pathogens for ObtainingIron from the Environment

Nidia Leon-Sicairos12 Ruth Reyes-Cortes1 Alma M Guadroacuten-Llanos1

Jesuacutes Maduentildea-Molina3 Claudia Leon-Sicairos4 and Adrian Canizalez-Romaacuten1

1Unidad de Investigacion de la Facultad de Medicina Universidad Autonoma de Sinaloa Cedros y SaucesSN Fracc Fresnos 80246 Culiacan SIN Mexico2Departamento de Investigacion del Hospital Pediatrico de Sinaloa ldquoDr Rigoberto Aguilar Picordquo Boulevard Constitucion SNColonia Jorge Almada 80200 Culiacan SIN Mexico3Facultad de Medicina Universidad Autonoma de Sinaloa Cedros y Sauces SN Fracc Fresnos 80246 Culiacan SIN Mexico4Doctorado en Biotecnologıa Facultad de Ciencias Quımico-Biologicas Universidad Autonoma de SinaloaAvenida de las Americas y Josefa Ortiz (Ciudad Universitaria) 80030 Culiacan SIN Mexico

Correspondence should be addressed to Nidia Leon-Sicairos nidialeonuasedumx

Received 7 November 2014 Accepted 9 February 2015

Academic Editor Francesca Mancianti

Copyright copy 2015 Nidia Leon-Sicairos et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Most microorganisms are destroyed by the host tissues through processes that usually involve phagocytosis and lysosomaldisruption However some organisms called intracellular pathogens are capable of avoiding destruction by growing insidemacrophages or other cells During infection with intracellular pathogenic microorganisms the element iron is required by boththe host cell and the pathogen that inhabits the host cell This minireview focuses on how intracellular pathogens use multiplestrategies to obtain nutritional iron from the intracellular environment in order to use this element for replication Additionallythe implications of these mechanisms for iron acquisition in the pathogen-host relationship are discussed

1 Introduction

Intracellular pathogens are organisms that are capable ofgrowing and reproducing inside host cells These pathogenscan be divided into facultative intracellular parasites and obli-gate intracellular parasites [1] Intracellular microorganismsare very important because they cause many human dis-eases resulting in significant morbidity and mortality Someexamples of infectious diseases of global importance thatare caused by intracellular microorganisms include tuber-culosis leprosy typhoid listeriosis Legionnairersquos diseasemalaria leishmaniasis Chagasrsquo disease and toxoplasmosisThe course of infection is frequently long lasting and eventu-ally results in chronic disease [2ndash4] Facultative intracellularparasites for example bacteria such as Francisella tularen-sis Listeria monocytogenes Salmonella typhiMycobacteriumspp and Neisseria meningitidis are capable of living andreproducing either inside or outside host cells Obligate

intracellular parasites cannot reproduce outside their hostcell which means that the parasitersquos reproduction is entirelyreliant on intracellular resources Obligate intracellular par-asites that infect humans include all viruses certain bacteriasuch as Chlamydia and Rickettsia certain protozoa such asTrypanosoma spp Plasmodium and Toxoplasma and fungisuch as Pneumocystis jirovecii [3] Facultative intracellularbacteria invade host cells when they can gain a selectiveadvantage in the host Bacteria that can enter and survivewithin eukaryotic cells are shielded from humoral antibodiesand can be eliminated only by a cellular immune response[5] Moreover once inside host cells bacteria must utilizespecializedmechanisms to protect themselves from the harshenvironment of the lysosomal enzymes encountered withinthe cells Some examples include the bacterium Legionellapneumophila which prefers the intracellular environment ofmacrophages for growth so it induces its own uptake andblocks lysosomal fusion by an undefined mechanism [6]

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 476534 17 pageshttpdxdoiorg1011552015476534

2 BioMed Research International

Rickettsia which destroys the phagosomal membranes (withwhich the lysosomes fuse) and Salmonella and Mycobac-terium spp which are resistant to intracellular killing byphagocytic and other cells [2] Other facultative intracellu-lar bacteria include enteroinvasive Escherichia coli Listeriamonocytogenes Neisseria spp and Shigella spp [2 7]

Obligate intracellular bacteria cannot live outside thehost cell Chlamydial cells are unable to carry out energymetabolism and lack many biosynthetic pathways and there-fore are entirely dependent on the host cell to supply themwith ATP (adenosine triphosphate) and other intermedi-ate molecules [8] Obligate intracellular bacteria cannot begrown in artificial media (agar platesbroths) in laboratoriesbut require viable eukaryotic host cells (eg cell cultureembryonated eggs and susceptible animals) Additional obli-gate intracellular bacteria include Coxiella burnetii Rickettsiaspp and others [8 9]

Microbial access to host nutrients is a fundamental aspectof infectious diseases Pathogens face complex dynamic nut-ritional host microenvironments that change with increasinginflammation and local hypoxia Because the host can activelylimit microbial access to its nutrient supply pathogens haveevolved various metabolic adaptations to successfully exploitavailable host nutrients to facilitate their own proliferation[10] Iron (Fe) is a key global regulator of cellular metabolismwhich makes Fe acquisition a focal point of the biologyof pathogen systems In the host environment the successor failure of Fe uptake processes impacts the outcome ofpathogenesis [11] After phagocytosis by macrophages intra-cellular bacteria are located in a membrane-bound vacuole(phagosome) but the ensuing trafficking of this vacuole andsubsequent bacterial survival strategies vary considerably Ifthe ingested bacteria have no intracellular survival mech-anisms the bacteria-containing phagosomes fuse with thelysosomal compartment and bacteria are digested within 15ndash30min For this reason the majority of intracellular bacteriaand other parasites must keep host cells alive as long aspossible while they are reproducing and growing [7 9] Togrow intracellular pathogens need nutrients such as the ironthatmight be scarce in the cell because this is usually retainedor stored by proteins

Pathogens that infect macrophages require Fe for growthbut during infection Fe is required by both the host cell andthe pathogen that inhabits the host cell [12] Macrophagesrequire Fe as a cofactor for the execution of important antimi-crobial effector mechanisms including the NADPH- (nicoti-namide adenine dinucleotide phosphate-oxidase-) depen-dent oxidative burst and the production of nitrogen radicalscatalyzed by the inducible nitric oxide synthase [13] Onthe other hand intracellular bacteria such as LegionellapneumophilaCoxiella burnetii Salmonella typhimurium andMycobacterium tuberculosis have an obligate requirement forFe to support their growth and survival inside host cells [14]In fact it has been documented that deprivation of Fe invivo and in vitro severely reduces the pathogenicity of Mtuberculosis C burnetii L pneumophila and S typhimurium[13ndash15]

2 Iron in the Human Host

Iron (Fe) is essential for the growth of all organisms Thehuman body contains 3ndash5 g of Fe distributed throughoutthe body in the protein hemoglobin tissues muscles bonemarrow blood proteins enzymes ferritin hemosiderin andtransport in plasma Iron (approximately 75) is contained inthe protein hemoglobin (Hb) and in other iron-bound pro-teins that are important for cellular processes and whateverremains in plasma (approximately 25) is bound to plasmaproteins such as transferrin (Tf) [16]

Dietary Fe has two main forms heme and nonhemePlants and iron-fortified foods contain nonheme Fe onlywhereas meat seafood and poultry contain both hemeand nonheme iron Heme iron which is formed when Fecombines with protoporphyrin IX contributes about 10to 15 of total Fe intakes in western populations [17]Intestinal absorption is the primary mechanism regulatingFe concentrations in the body Once ingested Fe absorptionoccurs predominantly in the duodenum and upper jejunumThemechanism of iron transport from the gut into the bloodstream remains unknown The first step of the pathway ofiron absorption in the human host involves reduction offerric Fe3+ to Fe2+ in the intestinal lumen by reductases orcytochrome b and transport of Fe2+ across the duodenalepithelium by the apical transporter DMT1 (divalent metaltransporter) In nonintestinal cells most Fe uptake occurs viaeither the classical clathrin-coated pathway utilizing transfer-rin receptors or the poorly defined transferrin receptor inde-pendent pathway Tf is the principal Fe storage protein thatstores and releases Fe inside cells that express the transferrinreceptor (TfR) The delivery of Fe from Tf is mediated by anacidic pH 55 of the endocytic vesicles carrying holo-Tf andTfR complexes Fe is then transported across the endosomalmembrane and utilized Excess intracellular Fe is sequesteredinto the protein Ft [18 19]

In a healthy individual Fe is largely intracellular seques-tered within Ft or as a cofactor of heme complexed toHb within erythrocytes Any extracellular free Fe is rapidlybound by circulating TfHb or heme that is released as a resultof natural erythrocyte lysis is captured by haptoglobin andhemopexin respectively Taken together these factors ensurethat vertebrate tissue is virtually devoid of free iron [21]Maintaining cellular Fe content requires precise mechanismsfor regulating its uptake storage and export The ironresponse elements or iron-responsive elements (IRP1 andIRP2) are the principal regulators of cellular Fe homeostasisin vertebrates IRPs are cytosolic proteins that bind to Fe-responsive elements (IREs) in the 51015840 or 31015840 untranslatedregions of mRNAs encoding proteins involved in Fe uptake(TfR1 DMT1) sequestration (H-ferritin subunit (FTH1) andL-ferritin subunit (FTL)) and export (ferroportin) Whencells are Fe deficient IRPs bind to 51015840 IREs in ferritin andferroportin mRNAs with high affinity to repress translationand to 31015840 IREs in TfR1 mRNA to block its degradation (Tf isinvolved in the transport or Fe) When Fe is in excess IRPsdo not bind to IREs increasing synthesis of Ft and ferroportin(proteins involved in the storage of Fe) while promoting thedegradation of TfR1 mRNA The coordinated regulation of

BioMed Research International 3

Daily diet contains 10ndash20mg iron

Macrophages 500mgRBC Hb 2300mg

Liver 200mg

Bone marrow 150mg Muscle fiber 350g

Total body ironcontains 35 g

PCBP

PCBP

PCBP

Fe2+

Fe2+

Fe3+

Ceruloplasmin

FerritinLysosomeProteasome

Hemoglobin-haptoglobinHeme-

Endosome

Erythrophagocytosis

Phagolysosome

Fpn

hemopexin

CD163

CD91Proteolysis

Nram

p1

DMT1

DMT1

Duodenumabsorption

Menstruation anddesquamation EC

iron losses 1-2 mg1-2 mg

Hepcidin

OH-1

Tf

Figure 1 Iron content in the human body and iron-containing proteins in a macrophage The average male adult contains approximately35 g of iron Approximately 2 g of iron is in hemoglobin 1 g in body is stored predominantly in the liver and the rest in myoglobin and otheriron-containing proteins Approximately 1 to 2mg of iron is lost each day by epithelial shedding in the gastrointestinal tract and the skinand through blood loss in menstruating women Western diets contain a much greater amount of iron (10 to 20mg) than what is absorbeddaily under normal circumstances (1 to 2mg) The macrophage is a key agent in iron homeostasis as well as in inflammatory hypoferremiaMacrophages in the spleen and in the liver (Kupffer cells) and perhaps elsewhere recognize damaged or senescent erythrocytes phagocytizethem and digest them to extract heme and eventually iron Macrophages can also scavenge heme and hemoglobin usually complexed withhemopexin and haptoglobin respectively and endocytosed by CD163 and CD91 respectively Whether phagocytosed in erythrocytes orendocytosed by scavenging hemoglobin undergoes proteolysis to release heme Heme is degraded by HO-1 to release iron which is exportedto the cytoplasm by DMT1 and probably also by Nramp1 Cytoplasmic chaperones family deliver iron for storage in the protein ferritinAlternatively iron from endosomes or phagolysosomes may also be delivered by an unknown carrier to ferroportin (Fpn) for export [20]

Fe uptake storage and export by the IRPs ensures that cellsacquire adequate Fe for their needs without reaching toxiclevels [22]

The ability of pathogens to obtain Fe from Tf Lf FtHb and other iron-containing proteins of their host iscentral to whether they live or die [14] This is because theseproteins are the main Fe sources for intracellular pathogensin the macrophage Iron homeostasis in the macrophageis determined by uptake processes through Lf Tf DMT-1 and phagocytosis of senescent erythrocytes as well asby export through ferroportin (Fpn) as we have discussedbefore Inside infectedmacrophages a pathogenrsquos access to Femay be limited by natural resistance-associated macrophageprotein 1 (SLC11A1 formerly Nramp1) SLC11A1 is a divalentmetal transporter recruited to the late endosomal and phago-somal membrane of macrophages and other professionalphagocytes Although SLC11A1 contributes to macrophagesrsquoefficiency in the recycling of erythrocyte-derived Fe themain function of SLC11A1 seems to be the protection againstmicrobes [20] Its gene is present in inbred strains of mice intwo allelic forms that determine the resistance or susceptibil-ity to several intracellular pathogens such as Mycobacteriumspp Salmonella spp and Leishmania spp [23] Some groupsof researchers have suggested that Fe is transported via thisprotein into the pathogen-containing phagosome causingthe death of the pathogen by catalyzing the formation of

reactive oxygen species (ROS) while others argue for Feefflux from the phagosome restricting pathogenic growthby Fe deprivation [23 24] Another Fe transporter that isexpressed in macrophages is Fpn This transporter is presentin the macrophage cytoplasmic membrane and is responsiblefor Fe export Overexpression of Fpn has been reported toinhibit the intramacrophagic growth of M tuberculosis andSalmonella enterica presumably through Fe deprivationThedetails of this mechanism are unclear [25 26] A scheme of Fesources in the human body and iron homeostasis inside themacrophage is shown in Figure 1

3 Mechanisms Used by IntracellularPathogens for Obtaining Iron A GeneralPoint of View

During infection pathogens are capable of altering thebattlefield to increase the abundance of potential Fe sourcesFor example bacterial cytotoxins damage host cells leadingto the release of Ft while hemolytic toxins from bacteria canlyse erythrocytes liberating Hb The resulting inflammatoryresponse includes the release of Lf from secondary granulescontained with polymorphonuclear leukocytes (PMNs) [1021 27] Pathogens are capable of exploiting these diverse Fesources through the elaboration of a variety of Fe acqui-sition systems In the case of extracellular pathogens they


can acquire Fe through receptor-mediated recognition ofTf Lf hemopexin hemoglobin or hemoglobin-haptoglobincomplexes [19 27] Alternatively secreted siderophores canremove Fe from Tf Lf or Ft whereupon siderophore-ironcomplexes are recognized by cognate receptors at the bacte-rial surface Siderophores are small ferric iron chelators thatbind with extremely high affinity (iron formation constants119870119889range from 10minus20 to 10minus50M) some of which can extract

iron from Tf and Lf [21] Analogously secreted hemophorescan remove heme from Hb or hemopexin and deliverheme to bacterial cells through binding with hemophorereceptors Siderophore mediated Fe acquisition is inhibitedby the innate immune protein siderocalin which bindssiderophores and prevents receptor recognition This hostdefense is circumvented through the production of stealthsiderophores that are modified in such a way as to preventsiderocalin binding [21 27]

For proper use of Fe extracellular or intracellular par-asites must possess at least the following systems (a) Fesensors for monitoring Fe concentration in the intracellu-lar environment (b) synthesis and release of high-affinitycompounds that can compete with host Fe binding proteinsfor Fe acquisition and storage or proteases to degrade thesehost Fe binding proteins (c) transportation of these Fe-loaded molecules and their assimilation and (d) regulationof the expression of proteins involved in iron metabolism inorder to maintain iron homoeostasis [27 28] Once ingestedby macrophages many intracellular parasites are taken upby phagosomes through endocytosis Thus the success ofintracellular parasites seems to be related mainly to theirability to take up Fe from the proteins Tf Hb hemoglobin-haptoglobin free heme and Ft Figure 2 shows intracellularparasites and Fe sources inside a macrophage

In order to take the Fe from Tf these systems can bedivided into three main categories siderophore-based sys-tems heme acquisition systems and transferrinlactoferrinreceptors

Upon removing Fe from host proteins iron-loaded side-rophores are bound by cognate receptors expressed at thebacterial surface The siderophore-iron complex is theninternalized into the bacterium and the Fe is released foruse as a nutrient source [21] Heme acquisition systemstypically involve surface receptors that recognize either hemeor heme bound to hemoproteins such as hemoglobin orhemopexin Heme is then removed from hemoproteinsand transported through the envelope of bacteria into thecytoplasm Once inside the cytoplasm the iron is releasedfrom heme through the action of heme oxygenases or reverseferrochelatase activity Bacterial pathogens can also elaboratesecreted heme-scavenging molecules that remove heme fromhost hemoproteins These molecules known as hemophoresare functionally analogous to siderophores but are proteinsthat target heme whereas siderophores are small moleculesthat target iron atoms [29] In addition to acquiring Fe fromTf and Lf through siderophore-based mechanisms somepathogens are capable of direct recognition of these hostproteins through receptors [21] These receptors are modeledto recognize Tf or Lf leading to Fe removal and subsequent

transport into the bacterial cytoplasm Additionally acidi-fication of the phagosome permits Fe release from Tf andprobably Lf and in this way some pathogens can gain accessto this element directly [19 21 30]

The following sections summarize the Fe acquisitionsystems used by some intracellular pathogens Table 1 showsFe sources mechanism of uptake transport and regulationused by intracellular parasites

4 Mechanism of Intracellular Pathogens forObtaining Iron from Host Sources

41 Francisella tularensis F tularensis the bacterial cause oftularemia is a virulent intracellular pathogen that can repli-cate inmultiple cell types Acidification of the phagosome andacquisition of Fe is essential for growth of F tularensis [31]An acidic pH promotes the release of Fe from host cell TfTo acquire the Fe from Tf F tularensis involves a receptorfor this protein (Transferrin receptor 1 TfR1) induction offerrireductases an iron membrane transporter (DMT-1) andiron regulatory proteins (IRP1 and IRP2) this is an activeFe acquisition system associated with a sustained increase ofthe labile Fe pool inside the macrophage [31] In additionF tularensis uses high-affinity transportation of ferrous Feacross the outer membrane via the proteins FupA and FslEFsIe appears to be involved in siderophore-mediated ferricFe uptake whereas FupA facilitates high-affinity ferrous Feuptake [32] It has been hypothesized that F tularensis usesthe Fe from Lf to sustain its growth however the mechanismof Fe acquisition from LF remains undetermined [33] It ismost likely that F tularensis can infect many types of cellsbecause it contains several strategies for Fe acquisition Ithas been reported that the expression of certain F tularensisvirulence genes is clearly regulated by Fe availability [34]

The expression of TfR1 is critical for the intracellularproliferation of Francisella This contrasts with infection ofmacrophages by Salmonella typhimurium which does notrequire expression of TfR1 for successful intracellular sur-vival Macrophages infected with Salmonella lack significantinduction of DMT-1 Steap3 and IRP1 and maintain theirlabile Fe pool at normal levels [12] Authors argue that thismight be explained by Salmonellarsquos intracellular localizationwithin an endosomal structure or perhaps by more efficientFe acquisition strategies compared to Francisella [12]

42 Salmonella spp Salmonella typhimurium is an invasivepathogen that causes diseases ranging from mild gastroen-teritis to enteric fever To establish a systemic infectionSalmonella sppmust invade the epithelial wall of the intestinebefore the bacteria are ingested by immune effector cellsand transported to lymph nodes the spleen and otherorgans Salmonella spp reside within modified phagosomesin macrophages where replication is promoted and killing isevaded Fe is an essential micronutrient for replication andSalmonella spp harbor various Fe acquisition systems suchas the siderophores enterobactin and salmochelin [35] Asiron sources Salmonella spp use Fe2+ Fe3+ heme ovotrans-ferrin and Tf [35 36] S Typhimurium acquires Fe2+ from


Early

Late

Phagolysosome

MycobacteriaEhrlichia

SalmonellaHistoplasma

Autophagolysosome

Nucleus

Mycoplasma

ChlamydiaToxoplasma

LegionellaBrucella

RickettsiaListeria

Coxiella Leishmania

ER

Autophagosome

Hemoglobin-haptoglobin

Tf

Lf

Tf

Lf

Tf

Lf

Tf

Lf

Tf

Lf

Ft

Fpn

Golgi

Figure 2 Intracellular parasites and iron sources inside of the macrophage During infection with intracellular bacteria iron is requiredby both the host cell and the pathogen that inhabits the host cell Macrophages require iron as a cofactor for the execution of importantantimicrobial effector mechanisms and so forth On the other hand intracellular bacteria also have an obligate requirement for iron tosupport their growth and survival inside cells Some pathogens are internalized into membranous compartments (endosomesphagosome)and then subsequently trafficked to the lysosome for degradation Intracellular pathogens have evolved specificmechanisms to survive withinthis intracellular environment for example Salmonella persists in the endocytic pathway and others escape the endo-lysosomal system andexist in the cytosol Other bacteria remain within a membranous envelope that may be a modified version of the endoplasmic reticulum (Lpneumophila) or a membranous compartment generated by the bacteria (Chlamydia) and so forth Intracellular pathogens can acquire ironbecause macrophages contain iron-proteins such as transferrin lactoferrin ferritin hemopexin hemoglobin or hemoglobin-haptoglobincomplexes in its different compartments

hemophagocyticmacrophages and also secretes siderophoresvia IroC and EntS to bind Fe3+ which is subsequentlytaken up by outer membrane receptors including IronN andFepA ABC transporters such as FepBCDG are responsiblefor the transport of siderophores through the cytoplasmicmembrane whereas molecular iron is taken up via Feo-mediated transmembrane transport [35 36]

During the infection process in vivo S typhimuriuminduces a number of virulence genes that are required tocircumvent host defenses andor acquire nutrients fromthe host A putative Fe transporter in Salmonella calledPathogenicity Island 1 or sitABCD has been character-ized The sitABCD operon is induced under Fe-deficientconditions in vitro and is repressed by Fur (ferric uptake

regulator)This locus is specifically induced in animalmodelsafter invasion of the intestinal epithelium suggesting thatSitABCD plays an important role in Fe acquisition in theanimal To regulate its Fe content Salmonella enterica serovarTyphimurium possesses four ferritins bacterioferritin (Bfr)ferritin A (FtnA) ferritin B (FtnB) and Dps The heme-containingBfr accounts for themajority of stored Fe followedby FtnA Inactivation of Bfr elevates the free intracellularFe concentration and enhances susceptibility to H

2O2stress

The DNA-binding Dps protein provides protection fromoxidative damage without affecting the free intracellular Feconcentration at steady state FtnB appears to be particularlyimportant for the repair of Fe-sulfur clusters of aconitasethat undergo oxidative damage and in contrast to Bfr and


Table 1 Iron sources and mechanisms of uptake transport and regulation used by intracellular parasites

Parasite Iron sources Mechanisms of ironacquisition Transport Regulation

Francisella tularensis

Tf Receptors (TfR1) FerrireductaseDMT-1 IRP1-IRP2

Fe3+ iron reductasesiderophores Fs1E

Fe2+ Receptors iron reductase FupALf Receptors iron reductase FerrireductaseDMT-1

Salmonella spp

Heme Heme-oxygenase-1 Porins FtnA FtnB FtnCFtnD

Tf siderophores (enterobactin FepBCDG sitABCDFur

Fe3+ enterochelin)IronN andFepA Feo

Fe2+ Phagocytosis

Chlamydia

Tf Receptors tonB analogue IRP-1IRE

Ft Receptors iron reductase Host Fe-transportpathways

Receptors ABC transport systemsSiderophores

Neisseria sppTf Receptors (TbpA TbpB) FetA FurLf Receptors (LbpA LbpB) MpeR

haptoglobin-Hb Siderophores (enterobactinSalmochelin) HmbR

Legionella pneumophilaFe3+ Siderophores Feo ABsystem FurFe2+ iron reductase PerRFur

Tf and Ft iron reductase Lpp 2867

Shigella spp

Tf Siderophores Feo ArcA and FNRFe3+ Fe3+ iron reductase Feo Sit luc FurHeme iron reductase ShuLF

Listeria monocytogenes

Hb HupDGC Fhu FriFurHemin HupDGC Fhu PerR

Ferric citrate iron reductase Ferric citrate systems

Fe-proteins Siderophores ironreductase Fur ABC transporters

Coxiella burnetii BacterioferritinsFur

Mycobacterium sppFerric dicitrate Salicylic acid IrtAB Bacterioferritins

Tf Lf Ft Citric acid Mramp FurA FurBSiderophores IdeR

Candida sppHeme Heme-binding protein

(Dap1) Sit1 (iron transporter)

TfFt

Fe3+ reductasesFe2+ transporter Sfu1

Hemin

Cryptococcus neoformansTf Iron reductase iron

permeases Cft1 and Cfo1 Cir1

Heme Hemophores Hemereceptors Cig1 and the ESCRT

Ft

Leishmania sppHeme Hemin LHR1 LIT1 transporter

Tf Fe3+ reductase 1 (LFR1)Lf

Trypanosoma spp Tf Receptors(TfR)endocytosis ESAG6 ESAG7 IRPIRE


FtnA is required for Salmonella virulence in mice MoreoverFtnB and Dps are repressed by the Fe-responsive regulatorFur and induced under conditions of Fe limitation whereasBfr and FtnA are maximally expressed when Fe is abundantThe absence of a conserved ferroxidase domain and thepotentiation of oxidative stress by FtnB in some strains thatlack Dps suggest that FtnB serves as a facile cellular reservoirof Fe2+ [37]

43 Chlamydia spp Chlamydia is an infection that is causedby the bacteriaChlamydia trachomatis It is themost commonsexually transmitted disease in the US with nearly 3 millioncases reported each year (the actual number of cases is likelymuch higher) The developmental cycle of C trachomatisincludes two forms an infectious elementary body (EB) anda reticulate body that multiplies within the inclusion bybinary fission A third developmental form is the persistentform which exists as a mechanism of survival under stressfulconditions Persistence is induced in response to changes inthe culture medium including amino acid or Fe deprivationand in the presence of antibiotics or cytokines such asgamma interferon (IFN) [38] It has been shown that Fe is anessential factor in the growth and survival of C trachomatisand C pneumoniae (this bacterium causes pneumonia) [39]Although homologues for bacterial siderophores are missingin the genome of this bacterium TfR expression does occurC trachomatis also appears to be missing a tonB analoguewhich would span the periplasm and is crucial in energytransfer to substrate-specific outer membrane transportersthat are used to bring Fe-siderophore complexes to the cellConsidering these apparent gaps in the genome one couldspeculate that the C trachomatis genome would need areductase on the inclusion membrane to transport Fe2+ fromthe eukaryotic cytosol into the inclusion C trachomatis andC pneumoniae appear to use the hostrsquos Fe transport pathwaysby attracting TfR and Ft to the phagosome [39] A report fromVardhan et al (2009) showed thatC trachomatis alters the Fe-regulatory protein-1 (IRP-1) binding capacity and modulatescellular iron homeostasis in HeLa-229 cells suggesting thatFe homeostasis is modulated in CT-infected HeLa cells at theinterface of acquisition and commensal use of Fe [40]

ATP-binding cassette (ABC) transport systems play arole in the acquisition of Fe and Fe-complexes amino acidssugars and other compounds They consist of a solubleperiplasmic protein that binds the targeted molecule andchanges conformation to close around the substrate Theperiplasmic binding protein moves to and binds the trans-membrane protein permease in receptor-ligandmechanismsAn ATP-binding lipoprotein binds to the ATP creating aconformational change in the permease complex that trans-ports the substrate into the cytoplasm In other pathogenicbacteria ABC transport systems that transport Fe zinc andmanganese into the cytoplasm include Tro from Treponemapallidum Yfe from Yersinia pestis and Fbp from Neisseriameningitidis [40] There is evidence that YtgA secretionoccurs in C trachomatis and YtgA does have high homologywith periplasmic binding proteins of the ABC transportsystems ytaA is a gene of 978 bp that resides in an operon

with ytgBVD YtgB and Ytg have predictable membrane-spanning domains and most likely form the pore of theABC transporter YtgA contains similarmetal-bindingmotifs(eg histidine tyrosine) to other metal-binding periplasmicproteins suggesting a role for YtgA as an Fe-binding periplas-mic protein in addition to its location on the chlamydialmembrane [41]

44 Neisseria spp Acquisition of Fe and Fe-complexes haslong been recognized as a major determinant in the patho-genesis of Neisseria spp and some of their high-affinity ironuptake systems are important virulence factors in bacteriaThese have been shown to play a major role in promoting thesurvival of the meningococcus within the host Most speciesare Gram-negative bacteria that are primarily commensalinhabitants or reside in the mucus membranes of mammalsThere are 12 Neisseria species of human origin with Nmeningitidis andN gonorrhoeae being important opportunis-tic pathogens These intracellular pathogens contain high-affinity iron uptake systems which allow meningococci toutilize the human host proteins Tf Lf Hb and haptoglobin-hemoglobin as sources of essential Fe [29 42] Althoughthe meningococci do not produce siderophores studiesindicate that meningococci may be able to use heterologoussiderophores secreted by other bacteria For some timeit has been reported that the gonococci could utilize fer-ric enterobactin enterobactin derivatives aerobactin andsalmochelin S2 in a FetA- and TonB-dependent manner[29] In N gonorrhoeae an outer membrane protein namedFetA (formerly FrpB) was recently described FetA is anouter membrane transporter and is part of an iron-regulatedoperon that encodes a periplasmic binding protein and thecomponents of a putative ABC transport system FetA hasdemonstrated low binding affinity and the transport of ferricenterobactin The binding contact of FetA for enterobactinwas much lower than that for other enterobactin receptorsand it was therefore proposed that this receptor couldinteract with high affinity to an as-yet unidentified phenolatesiderophore A homologous protein with 91 similarity togonococcal FetA has been identified in N meningitidis andpresumably functions in a similar manner [30 43] OnlyfetA and not the downstream genes require an iron-regulatorMpeR for regulationMpeR regulation is important because itmay aid in gonococcal immune evasionMpeRwas suggestedto modulate any change in mtrF expression that is neededfor full hydrophobic agent resistance AraC-like regulators ofN meningitidis are homologues of the N gonorrhoeae typeMpeR that is specific to the pathogenic Neisseria speciesBoth are induced during Fe limitation and this regulation isalso mediated by the Fur regulator The presence of MpeRin a regulatory cascade downstream of the Fur master Feregulator suggests that it is being expressed in the Fe limitingenvironment of the host where it may in turn regulate agroup of genes including the divergent Fe transport locusin response to signals that are important for infection [44]

Two proteins transferrin-binding protein A (TbpA)and transferrin-binding protein B (TbpB) function as thetransferrin receptor in N meningitidis TbpA and TbpB


are induced along with several other proteins in the outermembranes ofN meningitidis under Fe-restricted conditions[30] Initially an affinity isolation procedure using biotiny-lated transferrin was employed to demonstrate the presenceof two transferrin-binding proteins in N meningitidis Theproteins that bound transferrin were TbpA (formerly Tbp1)which is 98 kDa and TbpB (formerly Tbp2) which is 68 kDa[45] Among different meningococcal isolates the molecularmasses of TbpAandTbpB vary withTbpA ranging from93 to98 kDa and the more heterogenetic TbpB varying from 68 to85 kDa TbpA can be found in all strains Although it has notbeen characterized as well as the Tf receptor the Lf receptor isbelieved to be an important meningococcal virulence factor[29] The Lf receptor of N meningitidis like the Tf receptorconsists of two protein components LbpA and LbpB Initialexperiments using affinity isolation by Lf identified a 98-kDalactoferrin-binding protein named LbpA formerly known asIroA [46]

45 Legionella pneumophila Legionella pneumophila thecausative agent of Legionnairersquos disease is a facultativeintracellular parasite of human macrophages and freshwateramoebae This pathogenic bacterium is commonly found inwater thereby presenting a risk that it could be transmittedto humans via inhalation of contaminated aerosols L pneu-mophila resides in the phagosome although this phagosomedoes not fuse with endosomes and lysosomes and is at nearlyneutral pH during the early stages of the intracellular lifecycle It appears to fuse with low-pH cellular compartmentsduring the later stages of the infection [47]

The ability of L pneumophila to acquire host cell Fe ispivotal for the parasite to establish a successful intracellularinfection To occupy its intracellular niche this pathogenhas developed multiple Fe acquisition mechanisms theira AB locus which encodes a transporter for Fe-loadedpeptides the cytochrome c maturation ccm genes the Fe-regulated frgA whose product is homologous to aerobactinsynthetases legiobactin siderophores and two internal ferricreductases Robey and Cianciotto (2002) identified and char-acterized L pneumophila Feo AB which bears homology toE coli and Salmonella enterica serovar Typhimurium FeoABIn those bacteria FeoB has been shown to be a ferrous Fetransporter and FeoA is possibly involved in Fe2+ uptake [48]

In 2014 Portier and Cols discovered gene ipp 2867which was highly induced in Fe-restricted conditions Asequence analysis predicts that Lpp 2867 is a membraneprotein involved directly or indirectly in Fe2+ transport andis also a virulence factor [49]

46 Shigella spp Shigella is a Gram-negative bacterium ofthe Enterobacteriaceae family and is the etiological agentof bacillary dysentery or shigellosis Shigella encompassesfour subgroups (S flexneri S sonnei S dysenteriae andS boydii) and all species are able to grow in a varietyof environments including intracellularly in host epithelialcells Shigella has a number of different Fe transport systemsthat contribute to the bacteriumrsquos ability to grow in thesediverse environments [50] Siderophore Fe uptake systems

heme transporters and Fe3+ and Fe2+ transport systems arepresent in these bacteria and the genes encoding some ofthese systems appear to have spread among the Shigellaspecies by horizontal transmission [50 51] Fe is not onlyessential for the growth of Shigella but also plays an importantrole in the regulation of metabolic processes and virulencedeterminants in Shigella This regulation is mediated by therepressor protein Fur and the small RNA RyhB [52] Theonly Fe transport system that appears to be common to allmembers of the E coliShigella group is Feo Shigella spp havetransport systems for both ferric and ferrous iron The Fecan be taken up as free Fe or complexed with a variety ofcarriers All Shigella species have both the Feo and Sit systemsfor acquisition of Fe2+ and all have at least one siderophore-mediated system for transport of Fe3+ [53] Several of thetransport systems including Sit IucIutA (aerobactin syn-thesis and transport) Fec (ferric di-citrate uptake) and Shu(heme transport) are encoded within pathogenicity islandsThe presence and the genomic locations of these islands varyconsiderably among the Shigella species and even betweenisolates of the same species [53 54] The expression of the Fetransport systems is influenced by the concentration of Fe andby environmental conditions including the level of oxygenArcA and FNR regulate Fe transport gene expression as afunction of oxygen tension with the sit and iuc promotersbeing highly expressed in aerobic conditions while the feoFe2+ transporter promoter is most active under anaerobicconditions [52] The effects of oxygen are also observed ininfection of cultured cells by S flexneri the Sit and Iucsystems support plaque formation under aerobic conditionswhereas Feo allows plaque formation to occur anaerobically[52 53]

47 Listeria monocytogenes L monocytogenes is a Gram-positive intracellular pathogen responsible for the fatal dis-ease listeriosis Lmonocytogenes is recognized as a significantpublic health problemThe ability of this bacterium to acquireand utilize Fe is not only essential during infection butcan also support its growth and survival in many diverseenvironmental niches

L monocytogenes possesses at least 4 mechanisms thatenable Fe uptake (1) acquisition of protein-bound Fe thatinvolves the HupDGC protein (for the uptake of heminhemoglobin) or Fhu protein (involved in the uptake offerrichrome siderophores) inside the cell then Fe can bebound to the Fri protein (ferritin-like) Fur regulated (2)extracellular andor surface-bound Fe reductases (3) a citrateinducible ferric citrate uptake system and (4) siderophoreand siderophore-like systems [55]

The Listeria life cycle involves escape from the phago-some which is considered to be Fe-limiting and permitsproliferation in the host-cell cytosol where Fe-saturated Ftis stored It has been hypothesized that L monocytogeneshas access to Fe through increased expression of the PrfA-regulated virulence factors listeriolysin (LLO) and ActAwhich are used for phagosomal escape Increased Fe concen-trations result in the upregulation of internalin proteins InlAand InlB which are required for invasion [56]


Fe homeostasis in Listeria is controlled by the regulatoryprotein Fur It has been shown that expression of Fur is neg-atively regulated by PerR a Fur homologue that is involvedin the oxidative stress response Fourteen Fur-regulatedgenes have been identified in L monocytogenes includinggenes that encode Fe2+ transporters and ferrichrome ABCtransporters and proteins involved in Fe storage [56 57]

48 Coxiella burnetii Coxiella burnetii is the causative bac-terial agent of Q fever in humans and is one of the mostinfectious pathogens known Human infection with C bur-netii is generally a zoonosis that is acquired by inhalation ofcontaminated aerosols Q fever typically presents as an acuteself-limiting flu-like illness accompanied by pneumonia orhepatitis In 1 of cases a severe chronic infection can occurin which endocarditis is the predominant manifestation [58]It is essential for most pathogenic bacteria to overcome thelimitation of Fe in the intracellular host To overcome thislimitation bacteria maintain cell storage systems under thetight control of Fur It has been suggested that it is an absoluterequirement for C burnetii similar to L pneumophila toregulate Fe assimilation via the Fur regulon One studyrevealed that the Fur-regulon in C burnetii consists of a Fur-like protein (CBU1766) and the putative iron-binding proteinFrg1 (CBU0970) [59]

Iron plays a rather limited role in the pathogenesis of Cburnetii Reports have described the expression of a thiol-specific peroxidase (CBU0963) in C burnetii that belongsto the atypical 2-cysteine subfamily of peroxiredoxins alsodesignated as bacterioferritin comigratory proteins (BCPs)The implication is that this protein might protect DNA fromthe Fenton reaction [60] Comparison to L pneumophila aphylogenetic relative revealed that C burnetii rarely encodesany known Fe acquisition or storage proteins aside fromsome Fe dependent pathways as well as the heme biosynthe-sis pathway and proteins such as SodB

49 Mycobacterium spp Mycobacterium is a genus of Acti-nobacteria given its own family the Mycobacteriaceae Thegenus includes pathogens known to cause serious diseasesin mammals including tuberculosis (Mycobacterium tuber-culosis) and leprosy (Mycobacterium leprae) Similar to mostmicroorganisms Mycobacterium tuberculosis the causativeagent of tuberculosis requires Fe for essential metabolicpathways Like several other pathogenic bacteria it hasevolved an intricate mechanism of acquiring assimilatingand storing Fe which is a component that determines thefate of the pathogen inside the host [28] Because Fe isnot freely available in the host Mycobacteria must activelycompete for this metal to establish an infection but theymust also carefully control Fe acquisition as excess free Fecan be extremely toxic The molecules responsible for Feacquisition in mycobacteria include simple molecules suchas salicylic acid and citric acid apart from the two classes ofsiderophores

To acquire Fe mycobacteria produce siderophores (high-affinity Fe chelators)The lipophilic siderophores that remainassociated with the cell wall are called mycobactins and

the second class of siderophores includes polar forms that arereleased into the extracellular medium [28] These are calledcarboxymycobactins (released by pathogenic mycobacte-ria) and exochelins (released by nonpathogenic mycobacte-ria) M tuberculosis and M smegmatis produce salicylate-containing siderophores known as mycobactins There aretwo forms of mycobactins carboxymycobactin which isa water-soluble secreted molecule and the cell-associatedmycobactin which is a hydrophobicmolecule that is retainedon the cell surface In addition to mycobactinsM smegmatisalso produces a peptidic siderophore known as exochelinwhich is the predominant siderophore secreted by thismycobacterium under Fe limitation [28]

The identification of two genes that are annotated as fecBand fecB2 and that code proteins similar to FecB of Esche-richia coli suggests thatM tuberculosismay also utilize ferricdicitrate as an Fe source [61] Siderophores avidly bind Fe+3and can effectively compete with host Fe binding proteinsfor this metal Fe+3-carboxymycobactin can transfer Fe+3 tomycobactin or bring it into the cell via the iron-regulatedtransporter IrtAB The putative transporter encoded by fxu-ABC may transport Fe+3-exochelin complexes

Previous work has linked the ESX-3 system with theability of mycobacteria to adapt to Fe limitation ESX-3 isone of the five type VII secretion systems encoded by theMtuberculosis genome Studies that examined anM smegmatisexochelin synthesis mutant indicated an ESX-3 requirementfor Fe+3-mycobactin utilization The precise role of ESX-3 in Fe acquisition in M tuberculosis is unknown but itis clear that ESX-3 is necessary for adaptation to low Feconditions [62] On the other hand it has been documentedthat M tuberculosis increases microvesicles production inresponse to Fe restriction and that these microvesicles con-tain mycobactin which can serve as an iron donor and sup-ports replication of Fe-starved mycobacteria Consequentlythe results revealed that microvesicles play a role in Feacquisition in M tuberculosis and this can be critical forsurvival in the host Recent studies have demonstrated thatfailure to assemble the Fe acquisitionmachinery or to repressFe uptake has deleterious effects forM tuberculosis [28]

A protein that was speculated to be a mycobacterialiron transporter is the Mramp and this protein was able toincrease the uptake of Fe2+ and Zn2+ in a pH dependentmanner Mramp was expected to be a cation transporterwith no selective transport of Fe although additional reportsindicate that Mramp may act as a cation efflux pump [63]

Bacterioferritin-like molecules bfrA (a putative bacteri-oferritin) and bfrB (an Ft-like protein) have been identifiedin the M tuberculosis genome and are the principal Festorage molecules Their expression is induced under Fe-rich conditions and repressed under Fe-deprived conditionsTherefore it is speculated that this format allows the main-tenance of basal levels of bacterioferritin inside the pathogenso that any amount of excess Fe can be immediately storedin a bound form [64] Regulation of gene expression inM tuberculosis includes that of regulatory proteins stressresponse proteins enzymes and PE-PGRPPE proteins Thegenes that are upregulated under Fe-deprived conditions


included those that are responsible for acquisition of Fe suchas siderophores biosynthesis gene clusters mbt1 and mbt2and Fe regulated transporters of siderophores irtA irtBRv2895c and esx [28] Genes that are upregulated under Fe-rich conditions include bacterioferritin and ferritin (bfrA andbfrB) as they serve to store excess Fe as catalase-peroxidaseor katG and its regulator ferric uptake regulator A (FurA)[63]

There are two Fur proteins FurA and FurB After bindingferric iron FurA recognizes and binds to a 19-base-pairpseudopalindrome sequence of a specific DNA motif calledFur Box that is present upstream to a gene and acts as arepressor FurB on the other hand was later found to beregulated by zinc and not Fe and has been correctly referredto as Zur

IdeR an Fe-dependent repressor and activator is themajor regulatory protein involved in homeostasis in myco-bacteria Belonging to the Diphtheria toxin repressor fam-ily (DtxR) it acts as a homodimer with each monomerpossessing two binding sites for Fe Two homodimers withfour bound Fe ions recognize a 19-base-pair palindromicsequence and in Fe-replete conditions and negatively regulatethe expression of proteins required in Fe-depleted conditions[65] The genes or gene clusters essentially required duringFe starvation are effectively repressed by IeR These includethe siderophore synthesis gene cluster mbt1 mbt2 irtA irtBand Rv2895c Therefore there are certain proteins that aredifferentially regulated by Fe in an IdeR-independent fashionThese include lipoprotein IprE KatG 50S ribosomal proteinL22 and ATP synthase c chain two component responseregulators MTrA PE-PGRS proteins and NifU-like proteins[28] Fur and Fe-dependent repressors and activators or IdeRare the two key proteins that regulate expression of other Fe-dependent genes [28 63]

410 Candida spp Candida is a genus of yeast and is themostcommon cause of fungal infection worldwide [66 67] ManyCandida species are harmless commensals or endosymbiontsof hosts including humans however when mucosal barriersare disrupted or the immune system is compromised theycan invade tissues and cause disease [66] Among Candidaspecies C albicans is responsible for the majority of Candidabloodstream and mucosal infections However in recentyears there is an increasing incidence of infections causedby C glabrata and C rugosa C parapsilosis C tropicalisandC dubliniensis [66] Varied virulence factors and growingresistance to antifungal agents have contributed to theirpathogenicity [66 68]

Candida albicans can cause infections (candidiasis orthrush) in humans and other animals Between the commen-sal and pathogenic lifestyles this microorganism inhabitshost niches that differ markedly in the levels of bioavailableiron Once introduced into the bloodstream C albicans canacquire Fe from the molecules that are used by the host tosequester this metal [69] For example several groups haveidentified C albicans hemolytic activity capable of releasingHb fromhost erythrocytes FreeHbor its hemeheminmetal-porphyrin ring is bound by a hemoglobin receptor Rbt5

on the fungal cell surface followed by endocytosis of Rbt5-hemoglobin complexes and release of Fe2+ by the hemeoxidase Hmx1 [69] It has been reported that C albicansencodes four additional homologs of Rbt5 of which Rbt51 hasalso been demonstrated to bind to hemin [69]

C albicans can also utilize host Tf in vitro as a sole sourceof Fe probably through the involvement of a transferrinreceptor similar to certain bacterial pathogens It has beenreported that the Fe3+ derived from Tf is taken up by areductive iron uptake system that is conserved with the well-described high affinity iron uptake system of Saccharomycescerevisiae Fe3+ is first reduced to soluble Fe2+ by a cellsurface-associated ferric reductase [69] In coupled reactionsFe2+ is then oxidized and imported into the fungal cytoplasmby a multicopper ferroxidaseiron permease complex Calbicans encodes 17 putative ferric reductases five putativemulticopper ferroxidases and four putative ferric permeaseswith potential functions in reductive Fe uptake and differentsubsets of these enzymes are expressed under different invitro conditions Of the two ferric permeases only Ftr1 isexpressed when iron is limited and FTR1 is essential in amurine bloodstream infection model of virulence [69]

In tissues the Fe is mainly bound to Ft The Ft is foundinside of macrophages and epithelial cells This protein binds4500 Fe atoms and cytoplasmic iron-ferritin complexes aregenerally extremely stable It has been documented that Calbicans utilizes Ft as Fe source in vitro or directly fromepithelial cells in culture When this yeast was coculturedwith a human oral epithelial cell line the protein Ft wasfound bound onto their surface This Ft binding proteindenominated Als3 is located in the hyphae from C albicans[69] Als3 also plays important roles in C albicans biofilmformation [70] and adhesion to host epithelial and endothe-lial cells and induced endocytosis of hyphae [71] Thus Als3integrates Fe uptake and virulence functions but only in oralepithelial infection models This conclusion was obtainedwhen deletion of ALS3 abrogated C albicans virulence inthe oral epithelial infection model but not in a bloodstreaminfection model [69 72] Additionally it has been reportedthat in vitro fungal-mediated acidification of the laboratoryculture media is required to dissociate Fe3+ from ferritinFe3+ is transported into the fungal cytoplasm via the samereductive Fe uptake system described above for Ft [69]Figure 3 shows the iron acquisitions systems in C albicans

C albicans also possesses a third system of iron uptakebased in the use of siderophores however it is unclearwhether C albicans synthesizes its own siderophores Sidero-phore activity has been reported for this species but itsgenome does not encode the known fungal biosyntheticenzymes [69 73] Nevertheless C albicans has been demon-strated to utilize exogenous ferrichrome-type siderophoresvia the Sit1 siderophore importer Similar to ALS3 deletionof SIT1 abolishes C albicans virulence in a reconstitutedhuman epithelial infection model but not in a bloodstreaminfectionmodel [69 74] Finally it has been recently reportedthat Hap43 Sfu1 and Tup1 act coordinately and regulateiron acquisition iron utilization and other iron-responsivemetabolic activities in C albicans [75]


Fe3+Fe3+Fe3+

Fe3+Fe3+Fe3+

Fe3+Fe3+

Fe3+Fe3+Fe3+Fe3+

Fe3+Fe3+

Fe3+Fe3+Fe3+Fe3+ Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+Fe3+Fe3+

Fe3+

Heme

Hemin

Hemoglobin

Siderophore

SiderophoreFerritin

Als3

Ferritin Fre10

Fre10

Ftr1

receptor

receptor

receptor

HemoglobinRbt5

Rbt5 Hmx1 = Hemeoxygen

Vacuole

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+

Holo-T

fHolo

-Lf

Fe-reductaseFe-permease

Hmx1

TfR

Hypha

e

Cell wall

Xenosiderophore

Fe

Figure 3 Iron acquisitions systems in Candida albicans To acquire iron C albicans possesses three high-affinity iron acquisition systems(1) a reductive system responsible for iron exploitation from transferrin or ferritin or from the environment (2) a siderophore uptake systemresponsible for iron acquisition from a range of siderophores produced by other organisms and (3) a heme-iron uptake and degradationsystem capable of acquiring iron from hemoglobin and probably from heme-proteins

Candida glabrata is both a human fungal commensal andan opportunistic pathogen It is the second most commoncause of infection surpassed only by C albicans This yeastisan intracellular pathogen that can survive phagocytosisand replicates within the host cell C glabrata infection isextremely difficult to treat due to its intrinsic antifungalresistance to azoles The infections caused by this fungus areassociatedwith a highmortality rate Siderophore productionis common among most microorganisms and is a majormechanism of Fe solubilization and acquisition The veryhigh Fe-binding contact observed for siderophores of fungalorigin is approximately 1030M at pH 7 Several bacteria andfungi do not produce siderophores but have evolved trans-porters that allow them to utilize siderophores they them-selves do not produce These are called xenosiderophores[76]

Computational analysis of Sit1 identified sequence sig-natures that are characteristic of members of the MajorFacilitator Superfamily of Transporters In a study by Nevittand Thiele (2011) Sit1 is described as the sole siderophoreFe transporter in C glabrata and the study demonstratesthat this siderophore is critical for enhancing their survivalin the face of the microbicidal activities of macrophages[77] Within the Sit1 transporter a conserved extracellularsiderophore transporter domain (SITD) was identified thatis important for the siderophore-mediated ability of Cglabrata to resist macrophage killing and is dependent onmacrophage Fe status [77] They suggested that the hostrsquosiron status is a modifier of infectious disease that modulates

the dependence on a distinct mechanism of microbial Feacquisition Iron-regulated CaSit 1 shares high homologywith S cerevisiae siderophore transporters and its deletioncompromises utilization of fungal ferrichrome-type hydrox-amate siderophores The absence of an identifiable hemereceptor in C glabrata suggests that this pathogen mayrely predominantly on the solubilization of the circulatingexchangeable Fe pool to meet its requirements for Fe [76]

A study realized by Srivastava et al (2014) describedthe molecular analysis of a set of 13 C glabrata strainsthat were deleted for proteins and potentially implicated inFe metabolism The results revealed that the high-affinityreductive Fe uptake system is required for the utilizationof alternate carbon sources and for growth under both invitro Fe-limiting and in vivo conditions Further they showedfor the first time that the cysteine-rich CFEM domain-containing cell wall structural protein CgCcw14 and theputative hemolysin CgMam3 are essential for maintenanceof intracellular Fe content adherence to epithelial cells andvirulence [78] Additionally they present evidence that themitochondrial frataxin CgYfh1 is pivotal to Fe metabolismand conclude that high-affinity iron uptake mechanisms arecritical virulence determinants in C glabrata [78]

411 Cryptococcus neoformans Cryptococcus neoformans isa fungal pathogen and a leading cause of pulmonary andcentral nervous systemic mycosis in immunocompromisedindividuals such as HIV-infected patients For this reason


C neoformans is sometimes referred to as an opportunis-tic fungus It is a facultative intracellular pathogen Inhuman infection C neoformans is spread by inhalation ofaerosolized spores (basidiospores) and can disseminate tothe central nervous system where it can cause meningoen-cephalitis [79] In the lungs C neoformans are phagocytosedby alveolar macrophages Macrophages produce oxidativeand nitrosative agents creating a hostile environment tokill invading pathogens However some C neoformans cansurvive intracellularly in macrophages Intracellular survivalappears to be the basis for latency disseminated diseaseand resistance to eradication by antifungal agents [80]One mechanism by which C neoformans survives the hos-tile intracellular environment of the macrophage involvesupregulation of expression of genes involved in responsesto oxidative stress C neoformans has been considered anexcellent model fungal pathogen to study iron transportand homeostasis because of its intriguing connection withvirulence Growing evidence suggests that the fungus isable to utilize several different iron sources available in thehost and that the intracellular or extracellular localizationof the pathogen influences its iron acquisition strategy [80]C neoformans infects alveolar macrophages at this sitespecifically in the acidic phagolysosome free Fe2+ is releasedfrom the host Ft and TfThe reductive high-affinity Fe uptakesystem mediated by Cft1 and Cfo1 was characterized itsfunction was closely associated with the reduction of Fe3+ atthe cell surface by the reductase activity and it was limited inthe environment at neutral pH [79]

Therefore C neoformans could predominantly use aniron uptake system that is specifically responsive to the acidicintracellular niche although Fe deprivation at an acidic pHno longer reduced the growth of the cft1 and cfo1 mutantsMoreover a mutant lacking either CFT1 or CFO1 displayedattenuation of virulence and eventually caused disease ininfected mice These observations suggest that an as-yetunknown Fe uptake system which is independent of thereductive high-affinity iron uptake system may play a rolein the acidic host microenvironment in a phagolysosome[79] On the other hand C neoformans is able to utilize Tfthrough the reductive high-affinity iron uptake system andextracellular heme by Cig1 and the ESCRT complex howevermore studies should be carried out to understand how Cneoformans directly liberates Fe from Tf as well as Hb andother heme-containing proteins [80] It has been suggestedthat the gene CIR1 (Cryptococcus iron regulator) sharesstructural and functional features with other fungal GATA-type transcription factors for iron regulation [81] Figure 4shows the iron acquisitions systems in C neoformans

412 Leishmania spp Leishmaniasis is endemic in the tropicsand neotropics Clinical manifestations include skin lesionsranging from small cutaneous nodules to gross mucosal tis-sue destructionThe infection is transmitted to human beingsand animals by sandflies Leishmania parasites have a dige-netic life cycle alternating between the promastigote stagein the insect gut and the amastigote stage in macrophagesof mammalian hosts It has been postulated that Leishmania

cells are equipped with diverse Fe acquisition mechanismsand are capable of utilizing various Fe sources suggestingthat Fe acquisition is essential for pathogenicity and thatFe deprivation could be an effective strategy for controllingleishmanial infections [82]

Like many other intracellular pathogens Leishmaniamust be capable of acquiring Fe from the host milieu in orderto thrive In addition to Tf the growth and survival of Linfantum and L amazonensis amastigotes can be supportedby Fe derived from hemoglobin and hemin [83] The uptakeof heme by intramacrophagic L amazonensis amastigotes ismediated by the Leishmania heme response 1 (LHR1) proteinFurthermore intracellular L amazonensis also possessesa ferric reductase the Leismania ferric iron reductase 1(LFR1) which provides soluble Fe2+ for transport across theparasite plasma membrane by the ferrous iron transporterLeishmania iron transporter 1 (LIT1) [83 84] MoreoverLIT1-mediated Fe acquisition seems to be essential for thedifferentiation of L amazonensis parasites from the sandflypromastigote form to the macrophage-adapted amastigoteform [85]

Apart from themechanisms of direct iron internalizationLeishmania parasites can also subvert the hostrsquos Fe uptakesystems to their own advantage In fact L amazonensisamastigotes can obtain Tf by forcing the fusion of Tf-containing endosomes with the parasitophorous vacuole[86] Alternatively L donovani is capable of decreasingthe macrophagersquos labile Fe pool a process that triggers anincreased surface expression of transferrin receptor 1 andinternalization of Tf thus permitting continuous provisionof Fe to the parasite This decrease in the labile Fe pool ofactivated macrophages has recently been proposed to be theresult of the downregulation of the expression of SLC11A1 bya L donovani-secreted peroxidase Also in line with thesedata it has been reported that the expression of ferroportinis downregulated in the spleen of L donovani-infected micewhich may contribute to an increased accumulation of ironinside macrophages In Leishmania a transferrin receptor-based mechanism for Fe uptake was also initially postulatedbut this mechanismwas not confirmed by subsequent studies[87] Tf can reach the lysosome-like parasitophorous vacuoleswhere Leishmania resides in macrophages but it appears tofunctionmainly as a source of Fe3+ for the sequential action oftwo surface-associated parasite molecules the Fe3+ reductaseLFR1 and the LIT1 transporter which directly promote Fe2+uptake Intriguingly the T cruzi genome does not containan obvious LIT1 orthologue raising the possibility that thisFe2+-transporter represents a specific Leishmania adaptationto the lowFe environment of phagolysosomes [88]Mutationsin the lysosomal Fe efflux pump NRAMP1 confer suscep-tibility to Leishmania and other intravacuolar pathogensreinforcing the conclusion that Leishmania needs a high-affinity transporter such as LIT1 to compete effectively for Fewithin its parasitophorous vacuole [89] On the other handL amazonensis directly interferes with the Fe export functionof macrophages by inhibiting cell surface expression of Fpn1but the mechanism by which this is achieved is still unknown[90]


Holo-Tf

Hemophore

Heme

Cell wall contains melanin

CapsuleIron

uptakereductive

Highaffinity

Fe-

Fe-

permease(Cf1)

Cft2

M

M

oxidase

Fe-red1ndash8

Fe-reductase

Fe3+

Fe3+

Fe3+Fe3+

Fe3+Fe3+Fe3+Fe3+Fe3+

Fe3+

Fe3+Fe3+

Fe3+

Fe2+

Fe2+

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Low affinityuptake

Vacuole

ER

3-HAAsecreted

Hemereceptor

Laccase(Lac1 2)

Ferritin

Sit1siderophoretransporters

LIP

ESCRT pathway

(Cfo1)

Cfo2

Nucleus

Figure 4 Iron acquisitions systems in Cryptococcus neoformans C neoformans infects alveolar macrophages at this site specifically in theacidic phagolysosome free Fe2+ is released from the host Ft and Tf The reductive high-affinity Fe uptake system mediated by Cft1 and Cfo1plays a role in the reduction of Fe3+ at the cell surface by the reductase activity In addition C neoformans is able to utilize Tf throughthe reductive high-affinity iron uptake systemFinally for extracellular heme acquisition C neoformans relies on the complex Cft1Cfo1 axenosiderophore transporter (Sit1) and secreted and extracellular reductants (3-hydroxyanthranilic acid melanin)

413 Trypanosoma spp The amastigotes of the intracellularparasiteTrypanosoma cruzi take up Fe-loadedTfwhen grownin vitro but the physiological significance of this process isunclear [91] Tf is restricted to the lumen of the endocyticpathway and is therefore absent from the host cell cytosolwhere intracellular amastigotes replicate The bloodstreamform of Trypanosoma brucei acquires Fe from Tf by receptor-mediated endocytosis by a process that is regulated by Feavailability TrR is a heterodimeric complex encoded by twoexpression site-associated genes ESAG6 and ESAG7 andshares no homology with the homodimeric mammalian Tfreceptor The binding of one molecule of Tf requires theassociation of both ESAG6 and ESAG7 In mammalian cellsthe TfR mRNA is stabilized in iron-depleted cells due tothe binding of IRPs to specific IREs In T brucei this IRP-1relation is not essential for Fe regulation of ESAG6mRNA Inmammalian cells the closely related IPR-2 can independentlymediate the iron status via IREs However in trypanosomesthe presence of additional IRP-related proteins seems veryunlikely The T brucei genome contains only one IRP-relatedgene which suggests that a different mechanism a different

type of transacting factor is responsible for Fe sensing andregulation of transferrin receptor mRNA in this protozoan[91 92] However it is unknown how procyclic forms thatcannot bind Tf acquire Fe Additionally the bloodstream-form of T brucei acquires Fe by receptor-mediated endocy-tosis of host transferrin [93] The mechanism(s) by which Feis then transferred from the lysosome to the cytosol remainsunresolved [94]

5 Conclusions

The use of Fe as a cofactor in basic metabolic pathwaysis essential to both pathogenic microorganisms and theirhosts It is also a pivotal component of the innate immuneresponse through its role in the generation of toxic oxygenand nitrogen intermediates During evolution the sharedrequirement of micro- and macroorganisms for this impor-tant nutrient has shaped the pathogen-host relationship [14]Two general mechanisms of Fe acquisition in intracellu-lar parasites have been described siderophore-mediated Feacquisition by cognate receptors and receptor-mediated Fe


acquisition from host Fe-binding proteins [14] Intracellularmicroorganisms have evolved a variety of siderochromeswhich are special ligands that can dissolve insoluble Fe3+and facilitate its transport into the cell in order to acquireFe from Tf and other Fe-proteins in the host The successof intracellular parasites seems to be related mainly to theirability to take up Fe from the protein Tf [12] Once ingestedby macrophages intracellular parasites are taken up byphagosomes via endocytosis Acidification of the phagosomepermits the iron to be released fromTf and in this way somepathogens can gain access to this element [12]

Bacteria use the protein ferritin or bacterioferritin to storeFe These are ubiquitous Fe storage proteins that play a fun-damental role in cellular Fe homeostasis and have similaritieswith Ft that is found in mammals Bacterial Fts have thecapacity to store very large amounts of Fe as a Fe3+ mineralinside its central cavity In times of Fe deprivation somebacteria require that iron be released fromFtmineral stores inorder to maintain their metabolic rate and growth In timesof Fe repletion intracellular microorganisms must regulatethe genes required for Fe acquisition but this mechanismhas not been fully characterized [45 61] Transferrin andits receptor (TfR1) play an important role during infectionof macrophages with bacterial pathogens that prefer anintracellular lifestyle Expression of TfR1 can in turn bemodulated by bacterial infections Some pathogens activelyrecruit TfR1 to the bacterium-containing vacuole [29 45]

The notion is conceivable that intracellular pathogensreside in phagosomal compartments to modulate Fe regu-latory proteins thereby increasing their Fe availability butthis notion is still speculative The Fe acquisition processoften begins when cell surface receptors recognize Fe3+complexes and ultimately ends when cytoplasmic membrane(CM) transporters internalize and in some cases reduce themetal to Fe2+ which then enters cytoplasmicmetabolic pools[14] Despite many advances the exact role of Fe acquisitionsystems in vivo and their effects in pathogenic virulenceremain to be determined

Conflict of Interests

The authors declare that they have no conflict of interests

Acknowledgments

This work was supported by a grant from CONACYT(CB-2014-236546) and PROFAPI-UAS (2014) The authorsapologize to their colleagues whose work they were not ableto cover or cite in this brief review

References

[1] A Casadevall ldquoEvolution of intracellular pathogensrdquo AnnualReview of Microbiology vol 62 pp 19ndash33 2008

[2] K Hybiske and R S Stephens ldquoExit strategies of intracellularpathogensrdquo Nature Reviews Microbiology vol 6 no 2 pp 99ndash110 2008

[3] N Khan U Gowthaman S Pahari and J N Agrewala ldquoManip-ulation of costimulatory molecules by intracellular pathogens

veni vidi vicirdquo PLoS Pathogens vol 8 no 6 Article IDe1002676 2012

[4] Y Niki and T Kishimoto ldquoEpidemiology of intracellular patho-gensrdquo Clinical Microbiology and Infection vol 1 no 1 pp S11ndashS13 1996

[5] J Fredlund and J Enninga ldquoCytoplasmic access by intracellularbacterial pathogensrdquo Trends in Microbiology vol 22 no 3 pp128ndash137 2014

[6] E R Unanue ldquoIntracellular pathogens and antigen presenta-tion-new challenges with Legionella pneumophilardquo Immunityvol 18 no 6 pp 722ndash724 2003

[7] J A Theriot ldquoThe cell biology of infection by intracellularbacterial pathogensrdquo Annual Review of Cell and DevelopmentalBiology vol 11 no 1 pp 213ndash239 1995

[8] J Orfila ldquoDefinition of intracellular pathogensrdquo Clinical Micro-biology and Infection vol 1 supplement 1 pp S1ndashS2 1996

[9] V S Harley B S Drasar B Forrest B Krahn and GTovey ldquoInvasion strategies and intracellular growth of bacterialpathogensrdquo Biochemical Society Transactions vol 17 no 6 p1118 1989

[10] Y Abu Kwaik and D Bumann ldquoMicrobial quest for food invivo lsquonutritional virulencersquo as an emerging paradigmrdquo CellularMicrobiology vol 15 no 6 pp 882ndash890 2013

[11] E D Weinberg ldquoIron infection and neoplasiardquo Clinical Physi-ology and Biochemistry vol 4 no 1 pp 50ndash60 1986

[12] X Pan B Tamilselvam E J Hansen and S Daefler ldquoModula-tion of iron homeostasis in macrophages by bacterial intracel-lular pathogensrdquo BMCMicrobiology vol 10 article 64 2010

[13] C H Barton T E Biggs S T Baker H Bowen and P G PAtkinson ldquoNramp 1 a link between intracellular iron transportand innate resistance to intracellular pathogensrdquo Journal ofLeukocyte Biology vol 66 no 5 pp 757ndash762 1999

[14] H L Collins ldquoThe role of iron in infections with intracellularbacteriardquo Immunology Letters vol 85 no 2 pp 193ndash195 2003

[15] T F Byrd and M A Horwitz ldquoChloroquine inhibits the intra-cellularmultiplication of Legionella pneumophila by limiting theavailability of iron a potential new mechanism for the thera-peutic effect of chloroquine against intracellular pathogensrdquoTheJournal of Clinical Investigation vol 88 no 1 pp 351ndash357 1991

[16] A vonDrygalski and JWAdamson ldquoIronmetabolism inmanrdquoJournal of Parenteral and Enteral Nutrition vol 37 no 5 pp599ndash606 2013

[17] R Hurrell and I Egli ldquoIron bioavailability and dietary referencevaluesrdquo The American Journal of Clinical Nutrition vol 91 no5 pp 1461Sndash1467S 2010

[18] K Pantopoulos ldquoIron metabolism and the IREIRP regulatorysystem an updaterdquoAnnals of the New York Academy of Sciencesvol 1012 pp 1ndash13 2004

[19] G O Latunde-Dada ldquoIron metabolism microbes mouse andmanrdquo BioEssays vol 31 no 12 pp 1309ndash1317 2009

[20] T Ganz ldquoMacrophages and systemic iron homeostasisrdquo Journalof Innate Immunity vol 4 no 5-6 pp 446ndash453 2012

[21] E P Skaar ldquoThe battle for iron between bacterial pathogens andtheir vertebrate hostsrdquo PLoS Pathogens vol 6 no 8 Article IDe1000949 2010

[22] M W Hentze M U Muckenthaler and N C Andrews ldquoBal-ancing actsmolecular control ofmammalian ironmetabolismrdquoCell vol 117 no 3 pp 285ndash297 2004

[23] J K White P Mastroeni J-F Popoff C A W Evans and J MBlackwell ldquoSlc11a1-mediated resistance to Salmonella enterica


serovar Typhimurium and Leishmania donovani infections doesnot require functional inducible nitric oxide synthase or phago-cyte oxidase activityrdquo Journal of Leukocyte Biology vol 77 no 3pp 311ndash320 2005

[24] N Montalbetti A Simonin G Kovacs and M A HedigerldquoMammalian iron transporters families SLC11 and SLC40rdquoMolecular Aspects ofMedicine vol 34 no 2-3 pp 270ndash287 2013

[25] M Nairz D Haschka E Demetz and G Weiss ldquoIron at theinterface of immunity and infectionrdquo Frontiers in Pharmacol-ogy vol 5 article 152 2014

[26] H L Collins ldquoWithholding iron as a cellular defencemechanismmdashfriend or foerdquo European Journal of Immunologyvol 38 no 7 pp 1803ndash1806 2008

[27] M Nairz A Schroll T Sonnweber and GWeiss ldquoThe strugglefor ironmdasha metal at the host-pathogen interfacerdquo CellularMicrobiology vol 12 no 12 pp 1691ndash1702 2010

[28] S Banerjee A Farhana N Z Ehtesham and S E HasnainldquoIron acquisition assimilation and regulation in mycobacteriardquoInfection Genetics and Evolution vol 11 no 5 pp 825ndash838 2011

[29] A B Schryvers and I Stojiljkovic ldquoIron acquisition systems inthe pathogenicNeisseriardquoMolecularMicrobiology vol 32 no 6pp 1117ndash1123 1999

[30] N Noinaj N C Easley M Oke et al ldquoStructural basis for ironpiracy by pathogenic Neisseriardquo Nature vol 483 no 7387 pp53ndash58 2012

[31] A H Fortier D A Leiby R B Narayanan et al ldquoGrowth ofFrancisella tularensis LVS inmacrophages the acidic intracellu-lar compartment provides essential iron required for growthrdquoInfection and Immunity vol 63 no 4 pp 1478ndash1483 1995

[32] NM Perez andG Ramakrishnan ldquoThe reduced genome of theFrancisella tularensis live vaccine strain (LVS) encodes two ironacquisition systems essential for optimal growth and virulencerdquoPLoS ONE vol 9 no 4 Article ID e93558 2014

[33] O Olakanmi J S Gunn S Su S Soni D J Hassett and BE Britigan ldquoGallium disrupts iron uptake by intracellular andextracellular Francisella strains and exhibits therapeutic efficacyin a murine pulmonary infection modelrdquo Antimicrobial Agentsand Chemotherapy vol 54 no 1 pp 244ndash253 2010

[34] K Deng R J Blick W Liu and E J Hansen ldquoIdentification ofFrancisella tularensis genes affected by iron limitationrdquo Infectionand Immunity vol 74 no 7 pp 4224ndash4236 2006

[35] R Kingsley W Rabsch P Stephens M Roberts R Reissbrodtand P H Williams ldquoIron supplying systems of Salmonella indiagnostics epidemiology and infectionrdquo FEMS Immunologyand Medical Microbiology vol 11 no 4 pp 257ndash264 1995

[36] T A Nagy S M Moreland and C S Detweiler ldquoSalmonellaacquires ferrous iron from haemophagocytic macrophagesrdquoMolecular Microbiology vol 93 no 6 pp 1314ndash1326 2014

[37] J VelayudhanMCastor A Richardson K LMain-Hester andF C Fang ldquoThe role of ferritins in the physiology of Salmonellaenterica sv Typhimurium a unique role for ferritin B in iron-sulphur cluster repair and virulencerdquo Molecular Microbiologyvol 63 no 5 pp 1495ndash1507 2007

[38] J E Raulston ldquoResponse of Chlamydia trachomatis serovarE to iron restriction vitro and evidence for iron-regulatedchlamydial proteinsrdquo Infection and Immunity vol 65 no 11 pp4539ndash4547 1997

[39] H M Al-Younes T Rudel V Brinkmann A J Szczepek andT F Meyer ldquoLow iron availability modulates the course ofChlamydia pneumoniae infectionrdquo Cellular Microbiology vol 3no 6 pp 427ndash437 2001

[40] H Vardhan A R Bhengraj R Jha andA SMittal ldquoChlamydiatrachomatis alters iron-regulatory protein-1 binding capacityand modulates cellular iron homeostasis in heLa-229 cellsrdquoJournal of Biomedicine and Biotechnology vol 2009 Article ID342032 7 pages 2009

[41] J D Miller M S Sal M Schell J D Whittimore and JE Raulston ldquoChlamydia trachomatis YtgA is an iron-bindingperiplasmic protein in duced by iron restrictionrdquoMicrobiologyvol 155 no 9 pp 2884ndash2894 2009

[42] R J Yancey and R A Finkelstein ldquoAssimilation of iron bypathogenic Neisseria spprdquo Infection and Immunity vol 32 no2 pp 592ndash599 1981

[43] A Hollander A D Mercante W M Shafer and C NCornelissen ldquoThe iron-repressed AraC-like regulator MpeRactivates expression of fetA in Neisseria gonorrhoeaerdquo Infectionand Immunity vol 79 no 12 pp 4764ndash4776 2011

[44] L Fantappie V Scarlato and I Delany ldquoIdentification of thein vitro target of an iron-responsive AraC-like protein fromNeisseria meningitidis that is in a regulatory cascade with FurrdquoMicrobiology vol 157 no 8 pp 2235ndash2247 2011

[45] M T Criado M Pintor and C M Ferreiros ldquoIron uptake byNeisseria meningitidisrdquo Research in Microbiology vol 144 no 1pp 77ndash82 1993

[46] I Stojiljkovic J Larson V Hwa S Anic and S O MagdaleneldquoHmbR outermembrane receptors of pathogenicNeisseria sppiron- regulated hemoglobin-binding proteins with a high levelof primary structure conservationrdquo Journal of Bacteriology vol178 no 15 pp 4670ndash4678 1996

[47] M A Horwitz and S C Silverstein ldquoLegionnairesrsquo diseasebacterium (Legionella pneumophila) multiples intracellularly inhumanmonocytesrdquoThe Journal of Clinical Investigation vol 66no 3 pp 441ndash450 1980

[48] M Robey and N P Cianciotto ldquoLegionella pneumophila feoABpromotes ferrous iron uptake and intracellular infectionrdquo Infec-tion and Immunity vol 70 no 10 pp 5659ndash5669 2002

[49] E Portier H Zheng T Sahr et al ldquoIroTmavN a new iron-regulated gene involved in Legionella pneumophila virulenceagainst amoebae and macrophagesrdquo Environmental Microbiol-ogy 2014

[50] S M Payne ldquoIron and virulence in Shigellardquo Molecular Micro-biology vol 3 no 9 pp 1301ndash1306 1989

[51] C R Fisher N M L L Davies E E Wyckoff Z Feng EV Oaks and S M Payne ldquoGenetics and virulence associationof the Shigella flexneri sit iron transport systemrdquo Infection andImmunity vol 77 no 5 pp 1992ndash1999 2009

[52] S M Payne E E Wyckoff E R Murphy A G OglesbyM L Boulette and N M L Davies ldquoIron and pathogenesisof Shigella iron acquisition in the intracellular environmentrdquoBioMetals vol 19 no 2 pp 173ndash180 2006

[53] L J Runyen-Janecky S A Reeves E G Gonzales and S MPayne ldquoContribution of the Shigella flexneri sit iuc and feo ironacquisition systems to iron acquisition in vitro and in culturedcellsrdquo Infection and Immunity vol 71 no 4 pp 1919ndash1928 2003

[54] E E Wyckoff M L Boulette and S M Payne ldquoGenetics andenvironmental regulation of Shigella iron transport systemsrdquoBioMetals vol 22 no 1 pp 43ndash51 2009

[55] H PMcLaughlin C Hill and C G Gahan ldquoThe impact of ironon Listeria monocytogenes inside and outside the hostrdquoCurrentOpinion in Biotechnology vol 22 no 2 pp 194ndash199 2011

[56] R Bockmann C Dickneite B Middendorf W Goebel andZ Sokolovic ldquoSpecific binding of the Listeria monocytogenes


transcriptional regulator PrfA to target sequences requiresadditional factor(s) and is influenced by ironrdquoMolecularMicro-biology vol 22 no 4 pp 643ndash653 1996

[57] J Kreft and J A Vazquez-Boland ldquoRegulation of virulencegenes in Listeriardquo International Journal of Medical Microbiologyvol 291 no 2 pp 145ndash157 2001

[58] S Vanderburg M P Rubach J E B Halliday S CleavelandE A Reddy and J A Crump ldquoEpidemiology of Coxiellaburnetii infection in Africa a OneHealth systematic reviewrdquoPLoS Neglected Tropical Diseases vol 8 no 4 Article ID e27872014

[59] H L Briggs N Pul R Seshadri et al ldquoLimited role foriron regulation in Coxiella burnetii pathogenesisrdquo Infection andImmunity vol 76 no 5 pp 2189ndash2201 2008

[60] L D Hicks R Raghavan J M Battisti and M F Minnick ldquoADNA-binding peroxiredoxin of Coxiella burnetii is involved incountering oxidative stress during exponential-phase growthrdquoJournal of Bacteriology vol 192 no 8 pp 2077ndash2084 2010

[61] D Agranoff and S Krishna ldquoMetal ion transport and regulationin Mycobacterium tuberculosisrdquo Frontiers in Bioscience vol 9pp 2996ndash3006 2004

[62] A Serafini D Pisu G Palu G M Rodriguez and R Man-ganelli ldquoThe ESX-3 secretion system is necessary for iron andzinc homeostasis in Mycobacterium tuberculosisrdquo PLoS ONEvol 8 no 10 Article ID e78351 2013

[63] S Yellaboina S Ranjan VVindal andA Ranjan ldquoComparativeanalysis of iron regulated genes inMycobacteriardquo FEBS Lettersvol 580 no 11 pp 2567ndash2576 2006

[64] P V Reddy R V Puri A Khera and A K Tyagi ldquoIronstorage proteins are essential for the survival and pathogenesisof Mycobacterium tuberculosis in THP-1 macrophages and theguinea pig model of infectionrdquo Journal of Bacteriology vol 194no 3 pp 567ndash575 2012

[65] G M Rodriguez and I Smith ldquoMechanisms of iron regulationin Mycobacteria role in physiology and virulencerdquo MolecularMicrobiology vol 47 no 6 pp 1485ndash1494 2003

[66] A LMavor SThewes andBHube ldquoSystemic fungal infectionscaused byCandida species epidemiology infection process andvirulence attributesrdquoCurrentDrug Targets vol 6 no 8 pp 863ndash874 2005

[67] W R Jarvis ldquoEpidemiology of nosocomial fungal infectionswith emphasis on Candida speciesrdquo Clinical Infectious Diseasesvol 20 no 6 pp 1526ndash1530 1995

[68] M A Pfaller ldquoInfection control opportunistic fungal infec-tionsmdashthe increasing importance of Candida speciesrdquo InfectionControl and Hospital Epidemiology vol 10 no 6 pp 270ndash2731989

[69] H E J Kaba M Nimtz P P Muller and U BilitewskildquoInvolvement of the mitogen activated protein kinase Hog1pin the response of Candida albicans to iron availabilityrdquo BMCMicrobiology vol 13 article 16 2013

[70] R E Jeeves R P Mason A Woodacre and A M CashmoreldquoFerric reductase genes involved in high-affinity iron uptakeare differentially regulated in yeast and hyphae of Candidaalbicansrdquo Yeast vol 28 no 9 pp 629ndash644 2011

[71] R Martin B Wachtler M Schaller D Wilson and B HubeldquoHost-pathogen interactions and virulence-associated genesduring Candida albicans oral infectionsrdquo International Journalof Medical Microbiology vol 301 no 5 pp 417ndash422 2011

[72] I A Cleary S M Reinhard C Lindsay Miller et al ldquoCandidaalbicans adhesin Als3p is dispensable for virulence in themouse

model of disseminated candidiasisrdquoMicrobiology vol 157 no 6pp 1806ndash1815 2011

[73] E Lesuisse S A B Knight J-M Camadro and A DancisldquoSiderophore uptake by Candida albicans effect of serum treat-ment and comparisonwith Saccharomyces cerevisiaerdquoYeast vol19 no 4 pp 329ndash340 2002

[74] P Heymann M Gerads M Schaller F Dromer G Winkel-mann and J F Ernst ldquoThe siderophore iron transporter ofCan-dida albicans (Sit1pArn1p) mediates uptake of ferrichrome-type siderophores and is required for epithelial invasionrdquoInfection and Immunity vol 70 no 9 pp 5246ndash5255 2002

[75] P-C Hsu C-Y Yang and C-Y Lan ldquoCandida albicans Hap43is a repressor induced under low-iron conditions and is essentialfor iron-responsive transcriptional regulation and virulencerdquoEukaryotic Cell vol 10 no 2 pp 207ndash225 2011

[76] K Seider F Gerwien L Kasper et al ldquoImmune evasion stressresistance and efficient nutrient acquisition are crucial forintracellular survival of Candida glabratawithin macrophagesrdquoEukaryotic Cell vol 13 no 1 pp 170ndash183 2014

[77] T Nevitt and D J Thiele ldquoHost iron withholding demandssiderophore utilization for Candida glabrata to survive macro-phage killingrdquo PLoS Pathogens vol 7 no 3 Article ID e10013222011

[78] V K Srivastava K J Suneetha and R Kaur ldquoA systematicanalysis reveals an essential role for high-affinity iron uptakesystem haemolysin and CFEM domain-containing protein iniron homoeostasis and virulence inCandida glabratardquoBiochem-ical Journal vol 463 no 1 pp 103ndash114 2014

[79] J N Choi J Kim W H Jung and C H Lee ldquoInfluence of ironregulation on the metabolome of Cryptococcus neoformansrdquoPLoS ONE vol 7 no 7 Article ID e41654 2012

[80] W H Jung and E Do ldquoIron acquisition in the human fungalpathogen Cryptococcus neoformansrdquo Current Opinion in Micro-biology vol 16 no 6 pp 686ndash691 2013

[81] W H Jung A Sham R White and J W Kronstad ldquoIronregulation of themajor virulence factors in theAIDS-associatedpathogenCryptococcus neoformansrdquo PLoS Biology vol 4 no 12article e410 2006

[82] K Soteriadou P Papavassiliou C Voyiatzaki and J BoelaertldquoEffect of iron chelation on the in-vitro growth of Leishmaniapromastigotesrdquo Journal of Antimicrobial Chemotherapy vol 35no 1 pp 23ndash29 1995

[83] M EWilson T S LewisMAMillerM LMcCormick andBE Britigan ldquoLeishmania chagasi uptake of iron bound to lacto-ferrin or transferrin requires an iron reductaserdquo ExperimentalParasitology vol 100 no 3 pp 196ndash207 2002

[84] M EWilson RW Vorhies K A Andersen and B E BritiganldquoAcquisition of iron from transferrin and lactoferrin by theprotozoan Leishmania chagasirdquo Infection and Immunity vol 62no 8 pp 3262ndash3269 1994

[85] A R Flannery C Huynh B Mittra R A Mortara andN W Andrews ldquoLFR1 ferric iron reductase of Leishmaniaamazonensis is essential for the generation of infective parasiteformsrdquo Journal of Biological Chemistry vol 286 no 26 pp23266ndash23279 2011

[86] K J Saliba and K Kirk ldquoNutrient acquisition by intracellularapicomplexan parasites staying in for dinnerrdquo InternationalJournal for Parasitology vol 31 no 12 pp 1321ndash1330 2001

[87] I Jacques N W Andrews and C Huynh ldquoFunctional char-acterization of LIT1 the Leishmania amazonensis ferrous irontransporterrdquo Molecular and Biochemical Parasitology vol 170no 1 pp 28ndash36 2010


[88] V G Loo and R G Lalonde ldquoRole of iron in intracellulargrowth of Trypanosoma cruzirdquo Infection and Immunity vol 45no 3 pp 726ndash730 1984

[89] A R Flannery R L Renberg andNW Andrews ldquoPathways ofiron acquisition and utilization in LeishmaniardquoCurrent Opinionin Microbiology vol 16 no 6 pp 716ndash721 2013

[90] R Ben-Othman A R Flannery D C Miguel D M Ward JKaplan and N W Andrews ldquoLeishmania-mediated inhibitionof iron export promotes parasite replication in macrophagesrdquoPLoS Pathogens vol 10 no 1 Article ID e1003901 2014

[91] M F Lima and F Villalta ldquoTrypanosoma cruzi receptors forhuman transferrin and their rolerdquo Molecular and BiochemicalParasitology vol 38 no 2 pp 245ndash252 1990

[92] M J Soares and W de Souza ldquoEndocytosis of gold-labeledproteins and LDL byTrypanosoma cruzirdquo Parasitology Researchvol 77 no 6 pp 461ndash468 1991

[93] B Fast K Kremp M Boshart and D Steverding ldquoIron-dependent regulation of transferrin receptor expression inTrypanosoma bruceirdquo Biochemical Journal vol 342 no 3 pp691ndash696 1999

[94] J Mach J Tachezy and R Sutak ldquoEfficient iron uptake via areductivemechanism in procyclicTrypanosoma bruceirdquo Journalof Parasitology vol 99 no 2 pp 363ndash364 2013

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Rickettsia which destroys the phagosomal membranes (withwhich the lysosomes fuse) and Salmonella and Mycobac-terium spp which are resistant to intracellular killing byphagocytic and other cells [2] Other facultative intracellu-lar bacteria include enteroinvasive Escherichia coli Listeriamonocytogenes Neisseria spp and Shigella spp [2 7]

Obligate intracellular bacteria cannot live outside thehost cell Chlamydial cells are unable to carry out energymetabolism and lack many biosynthetic pathways and there-fore are entirely dependent on the host cell to supply themwith ATP (adenosine triphosphate) and other intermedi-ate molecules [8] Obligate intracellular bacteria cannot begrown in artificial media (agar platesbroths) in laboratoriesbut require viable eukaryotic host cells (eg cell cultureembryonated eggs and susceptible animals) Additional obli-gate intracellular bacteria include Coxiella burnetii Rickettsiaspp and others [8 9]

Microbial access to host nutrients is a fundamental aspectof infectious diseases Pathogens face complex dynamic nut-ritional host microenvironments that change with increasinginflammation and local hypoxia Because the host can activelylimit microbial access to its nutrient supply pathogens haveevolved various metabolic adaptations to successfully exploitavailable host nutrients to facilitate their own proliferation[10] Iron (Fe) is a key global regulator of cellular metabolismwhich makes Fe acquisition a focal point of the biologyof pathogen systems In the host environment the successor failure of Fe uptake processes impacts the outcome ofpathogenesis [11] After phagocytosis by macrophages intra-cellular bacteria are located in a membrane-bound vacuole(phagosome) but the ensuing trafficking of this vacuole andsubsequent bacterial survival strategies vary considerably Ifthe ingested bacteria have no intracellular survival mech-anisms the bacteria-containing phagosomes fuse with thelysosomal compartment and bacteria are digested within 15ndash30min For this reason the majority of intracellular bacteriaand other parasites must keep host cells alive as long aspossible while they are reproducing and growing [7 9] Togrow intracellular pathogens need nutrients such as the ironthatmight be scarce in the cell because this is usually retainedor stored by proteins

Pathogens that infect macrophages require Fe for growthbut during infection Fe is required by both the host cell andthe pathogen that inhabits the host cell [12] Macrophagesrequire Fe as a cofactor for the execution of important antimi-crobial effector mechanisms including the NADPH- (nicoti-namide adenine dinucleotide phosphate-oxidase-) depen-dent oxidative burst and the production of nitrogen radicalscatalyzed by the inducible nitric oxide synthase [13] Onthe other hand intracellular bacteria such as LegionellapneumophilaCoxiella burnetii Salmonella typhimurium andMycobacterium tuberculosis have an obligate requirement forFe to support their growth and survival inside host cells [14]In fact it has been documented that deprivation of Fe invivo and in vitro severely reduces the pathogenicity of Mtuberculosis C burnetii L pneumophila and S typhimurium[13ndash15]

2 Iron in the Human Host

Iron (Fe) is essential for the growth of all organisms Thehuman body contains 3ndash5 g of Fe distributed throughoutthe body in the protein hemoglobin tissues muscles bonemarrow blood proteins enzymes ferritin hemosiderin andtransport in plasma Iron (approximately 75) is contained inthe protein hemoglobin (Hb) and in other iron-bound pro-teins that are important for cellular processes and whateverremains in plasma (approximately 25) is bound to plasmaproteins such as transferrin (Tf) [16]

Dietary Fe has two main forms heme and nonhemePlants and iron-fortified foods contain nonheme Fe onlywhereas meat seafood and poultry contain both hemeand nonheme iron Heme iron which is formed when Fecombines with protoporphyrin IX contributes about 10to 15 of total Fe intakes in western populations [17]Intestinal absorption is the primary mechanism regulatingFe concentrations in the body Once ingested Fe absorptionoccurs predominantly in the duodenum and upper jejunumThemechanism of iron transport from the gut into the bloodstream remains unknown The first step of the pathway ofiron absorption in the human host involves reduction offerric Fe3+ to Fe2+ in the intestinal lumen by reductases orcytochrome b and transport of Fe2+ across the duodenalepithelium by the apical transporter DMT1 (divalent metaltransporter) In nonintestinal cells most Fe uptake occurs viaeither the classical clathrin-coated pathway utilizing transfer-rin receptors or the poorly defined transferrin receptor inde-pendent pathway Tf is the principal Fe storage protein thatstores and releases Fe inside cells that express the transferrinreceptor (TfR) The delivery of Fe from Tf is mediated by anacidic pH 55 of the endocytic vesicles carrying holo-Tf andTfR complexes Fe is then transported across the endosomalmembrane and utilized Excess intracellular Fe is sequesteredinto the protein Ft [18 19]

In a healthy individual Fe is largely intracellular seques-tered within Ft or as a cofactor of heme complexed toHb within erythrocytes Any extracellular free Fe is rapidlybound by circulating TfHb or heme that is released as a resultof natural erythrocyte lysis is captured by haptoglobin andhemopexin respectively Taken together these factors ensurethat vertebrate tissue is virtually devoid of free iron [21]Maintaining cellular Fe content requires precise mechanismsfor regulating its uptake storage and export The ironresponse elements or iron-responsive elements (IRP1 andIRP2) are the principal regulators of cellular Fe homeostasisin vertebrates IRPs are cytosolic proteins that bind to Fe-responsive elements (IREs) in the 51015840 or 31015840 untranslatedregions of mRNAs encoding proteins involved in Fe uptake(TfR1 DMT1) sequestration (H-ferritin subunit (FTH1) andL-ferritin subunit (FTL)) and export (ferroportin) Whencells are Fe deficient IRPs bind to 51015840 IREs in ferritin andferroportin mRNAs with high affinity to repress translationand to 31015840 IREs in TfR1 mRNA to block its degradation (Tf isinvolved in the transport or Fe) When Fe is in excess IRPsdo not bind to IREs increasing synthesis of Ft and ferroportin(proteins involved in the storage of Fe) while promoting thedegradation of TfR1 mRNA The coordinated regulation of




Liver 200mg



PCBP

PCBP

PCBP

Fe2+

Fe2+

Fe3+

Ceruloplasmin



Endosome

Erythrophagocytosis

Phagolysosome

Fpn

hemopexin

CD163

CD91Proteolysis

Nram

p1

DMT1

DMT1

Duodenumabsorption



Hepcidin

OH-1

Tf




















Early

Late

Phagolysosome



Autophagolysosome

Nucleus

Mycoplasma

ChlamydiaToxoplasma

LegionellaBrucella

RickettsiaListeria

Coxiella Leishmania

ER

Autophagosome


Tf

Lf

Tf

Lf

Tf

Lf

Tf

Lf

Tf

Lf

Ft

Fpn

Golgi





2O2stress









Salmonella spp




Fe2+ Phagocytosis

Chlamydia








Shigella spp











TfFt


Hemin




Ft











































Fe3+Fe3+Fe3+

Fe3+Fe3+Fe3+

Fe3+Fe3+

Fe3+Fe3+Fe3+Fe3+

Fe3+Fe3+


Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+Fe3+Fe3+

Fe3+

Heme

Hemin

Hemoglobin

Siderophore

SiderophoreFerritin

Als3

Ferritin Fre10

Fre10

Ftr1

receptor

receptor

receptor

HemoglobinRbt5


Vacuole

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+

Holo-T

fHolo

-Lf


Hmx1

TfR

Hypha

e

Cell wall

Xenosiderophore

Fe















Holo-Tf

Hemophore

Heme


CapsuleIron

uptakereductive

Highaffinity

Fe-

Fe-

permease(Cf1)

Cft2

M

M

oxidase

Fe-red1ndash8

Fe-reductase

Fe3+

Fe3+

Fe3+Fe3+


Fe3+

Fe3+Fe3+

Fe3+

Fe2+

Fe2+

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Low affinityuptake

Vacuole

ER

3-HAAsecreted

Hemereceptor

Laccase(Lac1 2)

Ferritin


LIP

ESCRT pathway

(Cfo1)

Cfo2

Nucleus




5 Conclusions








Acknowledgments


References













































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Liver 200mg



PCBP

PCBP

PCBP

Fe2+

Fe2+

Fe3+

Ceruloplasmin



Endosome

Erythrophagocytosis

Phagolysosome

Fpn

hemopexin

CD163

CD91Proteolysis

Nram

p1

DMT1

DMT1

Duodenumabsorption



Hepcidin

OH-1

Tf




















Early

Late

Phagolysosome



Autophagolysosome

Nucleus

Mycoplasma

ChlamydiaToxoplasma

LegionellaBrucella

RickettsiaListeria

Coxiella Leishmania

ER

Autophagosome


Tf

Lf

Tf

Lf

Tf

Lf

Tf

Lf

Tf

Lf

Ft

Fpn

Golgi





2O2stress









Salmonella spp




Fe2+ Phagocytosis

Chlamydia








Shigella spp











TfFt


Hemin




Ft











































Fe3+Fe3+Fe3+

Fe3+Fe3+Fe3+

Fe3+Fe3+

Fe3+Fe3+Fe3+Fe3+

Fe3+Fe3+


Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+Fe3+Fe3+

Fe3+

Heme

Hemin

Hemoglobin

Siderophore

SiderophoreFerritin

Als3

Ferritin Fre10

Fre10

Ftr1

receptor

receptor

receptor

HemoglobinRbt5


Vacuole

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+

Holo-T

fHolo

-Lf


Hmx1

TfR

Hypha

e

Cell wall

Xenosiderophore

Fe















Holo-Tf

Hemophore

Heme


CapsuleIron

uptakereductive

Highaffinity

Fe-

Fe-

permease(Cf1)

Cft2

M

M

oxidase

Fe-red1ndash8

Fe-reductase

Fe3+

Fe3+

Fe3+Fe3+


Fe3+

Fe3+Fe3+

Fe3+

Fe2+

Fe2+

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Low affinityuptake

Vacuole

ER

3-HAAsecreted

Hemereceptor

Laccase(Lac1 2)

Ferritin


LIP

ESCRT pathway

(Cfo1)

Cfo2

Nucleus




5 Conclusions








Acknowledgments


References













































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology














Early

Late

Phagolysosome



Autophagolysosome

Nucleus

Mycoplasma

ChlamydiaToxoplasma

LegionellaBrucella

RickettsiaListeria

Coxiella Leishmania

ER

Autophagosome


Tf

Lf

Tf

Lf

Tf

Lf

Tf

Lf

Tf

Lf

Ft

Fpn

Golgi





2O2stress









Salmonella spp




Fe2+ Phagocytosis

Chlamydia








Shigella spp











TfFt


Hemin




Ft











































Fe3+Fe3+Fe3+

Fe3+Fe3+Fe3+

Fe3+Fe3+

Fe3+Fe3+Fe3+Fe3+

Fe3+Fe3+


Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+Fe3+Fe3+

Fe3+

Heme

Hemin

Hemoglobin

Siderophore

SiderophoreFerritin

Als3

Ferritin Fre10

Fre10

Ftr1

receptor

receptor

receptor

HemoglobinRbt5


Vacuole

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+

Holo-T

fHolo

-Lf


Hmx1

TfR

Hypha

e

Cell wall

Xenosiderophore

Fe















Holo-Tf

Hemophore

Heme


CapsuleIron

uptakereductive

Highaffinity

Fe-

Fe-

permease(Cf1)

Cft2

M

M

oxidase

Fe-red1ndash8

Fe-reductase

Fe3+

Fe3+

Fe3+Fe3+


Fe3+

Fe3+Fe3+

Fe3+

Fe2+

Fe2+

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Low affinityuptake

Vacuole

ER

3-HAAsecreted

Hemereceptor

Laccase(Lac1 2)

Ferritin


LIP

ESCRT pathway

(Cfo1)

Cfo2

Nucleus




5 Conclusions








Acknowledgments


References













































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








Salmonella spp




Fe2+ Phagocytosis

Chlamydia








Shigella spp











TfFt


Hemin




Ft











































Fe3+Fe3+Fe3+

Fe3+Fe3+Fe3+

Fe3+Fe3+

Fe3+Fe3+Fe3+Fe3+

Fe3+Fe3+


Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+Fe3+Fe3+

Fe3+

Heme

Hemin

Hemoglobin

Siderophore

SiderophoreFerritin

Als3

Ferritin Fre10

Fre10

Ftr1

receptor

receptor

receptor

HemoglobinRbt5


Vacuole

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+

Holo-T

fHolo

-Lf


Hmx1

TfR

Hypha

e

Cell wall

Xenosiderophore

Fe















Holo-Tf

Hemophore

Heme


CapsuleIron

uptakereductive

Highaffinity

Fe-

Fe-

permease(Cf1)

Cft2

M

M

oxidase

Fe-red1ndash8

Fe-reductase

Fe3+

Fe3+

Fe3+Fe3+


Fe3+

Fe3+Fe3+

Fe3+

Fe2+

Fe2+

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Low affinityuptake

Vacuole

ER

3-HAAsecreted

Hemereceptor

Laccase(Lac1 2)

Ferritin


LIP

ESCRT pathway

(Cfo1)

Cfo2

Nucleus




5 Conclusions








Acknowledgments


References













































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








































Fe3+Fe3+Fe3+

Fe3+Fe3+Fe3+

Fe3+Fe3+

Fe3+Fe3+Fe3+Fe3+

Fe3+Fe3+


Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+Fe3+Fe3+

Fe3+

Heme

Hemin

Hemoglobin

Siderophore

SiderophoreFerritin

Als3

Ferritin Fre10

Fre10

Ftr1

receptor

receptor

receptor

HemoglobinRbt5


Vacuole

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Fe2+

Holo-T

fHolo

-Lf


Hmx1

TfR

Hypha

e

Cell wall

Xenosiderophore

Fe















Holo-Tf

Hemophore

Heme


CapsuleIron

uptakereductive

Highaffinity

Fe-

Fe-

permease(Cf1)

Cft2

M

M

oxidase

Fe-red1ndash8

Fe-reductase

Fe3+

Fe3+

Fe3+Fe3+


Fe3+

Fe3+Fe3+

Fe3+

Fe2+

Fe2+

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Low affinityuptake

Vacuole

ER

3-HAAsecreted

Hemereceptor

Laccase(Lac1 2)

Ferritin


LIP

ESCRT pathway

(Cfo1)

Cfo2

Nucleus




5 Conclusions








Acknowledgments


References













































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology









Holo-Tf

Hemophore

Heme


CapsuleIron

uptakereductive

Highaffinity

Fe-

Fe-

permease(Cf1)

Cft2

M

M

oxidase

Fe-red1ndash8

Fe-reductase

Fe3+

Fe3+

Fe3+Fe3+


Fe3+

Fe3+Fe3+

Fe3+

Fe2+

Fe2+

Fe2+

Fe2+

Fe2+Fe2+

Fe2+

Low affinityuptake

Vacuole

ER

3-HAAsecreted

Hemereceptor

Laccase(Lac1 2)

Ferritin


LIP

ESCRT pathway

(Cfo1)

Cfo2

Nucleus




5 Conclusions








Acknowledgments


References













































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology







Acknowledgments


References













































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Review Article Strategies of Intracellular Pathogens for...

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