Iron in Infection and Immunity

In the paper

“Bacterial pathogens store iron in one of three types of proteins: ferritin, bacterioferritins, and Dps proteins.”

What the sources say

• Supported

  Section 3.1 identifies ferritins, bacterioferritins, and Dps proteins as the three recognized types of bacterial iron-storage protein. Section 3.2 adds a qualification: Dps can store iron, although its primary role in E. coli may be DNA protection. (LLM, conf=0.90)

  cites Andrews et al., 2003 source

In the paper

“Acquisition of heme by the Isd system is critical for S. aureus pathogenesis (Cassat and Skaar, 2012).”

What the sources say

• Not checked yetcites Cassat and Skaar, 2012 source

In the paper

“In addition to mitigating toxicity associated with hypo- or hyperferremia, regulation of iron distribution serves as an innate immune mechanism against invading pathogens.”

In the paper

“Patients with iron overload from hemochromatosis and thalassemia are more susceptible to infection with Yersinia spp., Listeria monocytogenes, and Vibrio vulnificus, among others (Long et al., 2003).”

What the sources say

• Not checked yetcites Long et al., 2003

In the paper

“Nramp1 (natural resistance associated macrophage protein-1) is a divalent metal ion transporter that has been proposed to reduce iron content in early endosomes, thereby limiting availability to intracellular pathogens in this compartment (Jabado et al., 2000; Vidal et al., 1995).”

What the sources say

• Not checked yetcites Jabado et al., 2000 source
• Not checked yetcites Vidal et al., 1995 source

In the paper

“However, hemolytic pathogens must subsequently compete with haptoglobin and hemopexin, host glycoproteins that scavenge liberated hemoglobin and heme, respectively (Figure 1D).”

In the paper

“Inside the macrophage, Mtb disrupts phagolysosomal maturation, an iron-dependent process critical for pathogen survival (Olakanmi et al., 2000).”

What the sources say

• Not checked yetcites Olakanmi et al., 2000 source

In the paper

“Siderophores can therefore effectively outcompete host transferrin, which binds iron with an association constant of approximately 1036.”

What the sources say

• Not checked yetcites Bullen JJ, 1999

In the paper

“Chelation therapy with desferrioxamine may therefore increase the risk of infection in patients with iron overload (Kim et al., 2007).”

What the sources say

• Not checked yetcites Kim et al., 2007 source

In the paper

“The importance of strict regulation of iron metabolism is underscored by the pathologic consequences of iron overload syndromes. Individuals suffering from iron overload not only experience cellular damage from adverse redox chemistry of free iron, but also are at enhanced risk of infection.”

In the paper

“Hepcidin is a major orchestrator of the hypoferremic response to infection.”

In the paper

“Accordingly, siderocalin-deficient mice display an enhanced susceptibility to E. coli septicemia (Flo et al., 2004).”

What the sources say

• Not checked yetcites Flo et al., 2004 source

In the paper

“Bacterial siderophore production is typically regulated in an iron-dependent manner by either the ferric uptake regulator (Fur) or the diphtheria toxin regulator (DtxR). Both Fur and DtxR repress transcription of target genes in the presence of iron.”

In the paper

“In addition to hepcidin production in the liver, neutrophils and macrophages synthesize hepcidin in response to infectious agents, allowing for modulation of iron availability at the infectious focus (Peyssonnaux et al., 2006).”

What the sources say

• Not checked yetcites Peyssonnaux et al., 2006 source

In the paper

“The production of siderophores contributes to the virulence of a variety of pathogens, including S. aureus, Escherichia coli, Legionella pneumophila, and Bacillus anthracis, among others (Cassat and Skaar, 2012).”

What the sources say

• Not checked yetcites Cassat and Skaar, 2012 source

In the paper

“Of note, S. aureus the Isd system has evolved to utilize human hemoglobin preferentially over hemoglobin from other species.”

What the sources say

• Not checked yetcites Pishchany et al., 2010 source

In the paper

“Two major classes of bacterial heme acquisition systems exist: direct heme uptake systems and hemophore-dependent systems (Anzaldi and Skaar, 2010).”

What the sources say

• Not checked yetcites Anzaldi and Skaar, 2010 source

In the paper

“Pyoverdin, one of two siderophores produced by Pseudomonas aeruginosa, elicits host cell death in Caenorhabditis elegans by induction of a hypoxic response dependent on the iron-responsive transcription factor HIF-1 (Kirienko et al., 2013).”

What the sources say

• Not checked yetcites Kirienko et al., 2013 source

In the paper

“Bacterial pathogens must therefore possess mechanisms to overcome iron-withholding defenses in order to successfully colonize humans.”

In the paper

“Activation of phagocytes at the site of infection also limits iron availability to intracellular pathogens (Figure 2C). Pattern recognition receptor binding and pro-inflammatory cytokines decrease the expression of transferrin receptors on the surface of phagocytes, while enhancing expression of the intracellular iron transporter, Nramp1.”

In the paper

“Nevertheless, bacterial pathogens employ one or a combination of five primary mechanisms to satisfy the requirement for nutrient iron (Figure 3).”

In the paper

“Transferrin binding is important for the virulence of Neisseria spp., as tbp mutants are avirulent in a human model of infection (Cornelissen et al., 1998).”

What the sources say

• Not checked yetcites Cornelissen et al., 1998 source

In the paper

“A similar hypoferremic response was noted upon intravenous injection with sterile turpentine, suggesting that inflammation, rather than a specific microbial product was responsible for declining plasma iron levels (Cartwright et al., 1946).”

What the sources say

• Not checked yetcites Cartwright et al., 1946 source

In the paper

“However, the redox potential of iron also generates cellular toxicity under conditions of iron overload. Reactive oxygen intermediates are generated during the course of normal cellular homeostasis. In the presence of such reactive oxygen species, iron can catalyze the Fenton reaction to generate hydroxyl radicals that damage lipids, DNA, and protein.”

In the paper

“Although it encodes other iron acquisition pathways, the preferred iron source for S. aureus is heme (Skaar et al., 2004b).”

What the sources say

• Not checked yetcites Skaar et al., 2004b

In the paper

“Some bacterial pathogens, such as Haemophilus influenzae, are incapable of endogenous heme biosynthesis and therefore depend exclusively on exogenous heme acquisition.”

In the paper

“For instance, this strategy is used by B. anthracis and Salmonella Typhimurium, both of which produce modified siderophores that are not bound by siderocalin (Abergel et al., 2006; Raffatellu et al., 2009).”

What the sources say

• Not checked yetcites Abergel et al., 2006 source
• Not checked yetcites Raffatellu et al., 2009 source

In the paper

“Accordingly, transgenic mice expressing human hemoglobin alleles are more susceptible to S. aureus infection (Pishchany et al., 2010).”

What the sources say

• Not checked yetcites Pishchany et al., 2010 source

In the paper

“However, Nramp1 has also been suggested to facilitate the delivery of iron into late endosomes and lysosomes, harnessing the toxic properties of iron to control microbial growth (Zwilling et al., 1999).”

What the sources say

• Not checked yetcites Zwilling et al., 1999 source

In the paper

“Similarly, both Dps and the ferritin FtnB are required for full virulence of S. Typhimurium (Halsey et al., 2004; Velayudhan et al., 2007).”

What the sources say

• Not checked yetcites Halsey et al., 2004 source
• Not checked yetcites Velayudhan et al., 2007 source

In the paper

“Inactivation of the genes encoding the HrtAB transporter leads to impairment of growth in media containing high concentrations of heme (Stauff et al., 2008).”

What the sources say

• Not checked yetcites Stauff et al., 2008 source

In the paper

“Pathogenic microbes use mechanisms analogous to those in human iron homeostasis to maintain a proper distribution of iron: storage, regulation of uptake, and regulation of efflux.”

In the paper

“In other parasitic infections, the connection between pathogen and host iron homeostasis is less direct, but many human parasites rely on host iron and iron-containing compounds to cause disease.”

In the paper

“By maintaining proper intracellular iron distribution, these compounds promote germination and resistance to oxidative stress, and are required for full virulence in a mouse model of invasive infection (Schrettl et al., 2007).”

What the sources say

• Not checked yetcites Schrettl et al., 2007 source

In the paper

“However, induction of cytoprotective iron-detoxification strategies may paradoxically limit innate immunity.”

In the paper

“C. albicans is also capable of exploiting host ferritin as an iron source using reductive uptake.”

In the paper

“A third mechanism of fungal iron acquisition is the uptake of heme.”

In the paper

“In general, three mechanisms exist for iron acquisition in fungi: reductive uptake, siderophore-mediated uptake, and heme acquisition (Howard, 1999).”

What the sources say

• Not checked yetcites Howard, 1999 source

In the paper

“In addition to roles in hyphal formation, adhesion, and invasion of host cells, the candidal protein Als3 serves as a ferritin receptor, demonstrating that iron acquisition components may serve multiple roles in virulence (Almeida et al., 2008).”

What the sources say

• Not checked yetcites Almeida et al., 2008 source

In the paper

“Although the molecule(s) exported by S. aureus HrtAB to alleviate heme toxicity is unknown, the Lactococcus lactis HrtAB transporter specifically effluxes heme (Lechardeur et al., 2012).”

What the sources say

• Not checked yetcites Lechardeur et al., 2012 source

In the paper

“Mycobacteria circumvent these iron-withholding defenses by directly modulating ferroportin expression (Van Zandt et al., 2008).”

What the sources say

• Not checked yetcites Van Zandt et al., 2008 source

In the paper

“One of the earliest antimicrobials used for treatment of tuberculosis, p-aminosalicylic acid (PAS), inhibits mycobactin biosynthesis (Ratledge and Brown, 1972).”

What the sources say

• Not checked yetcites Ratledge and Brown, 1972 source

In the paper

“S. aureus heme toxicity occurs in part due to membrane-associated oxidative damage, which is potentiated by the electron carrier menaquinone (Wakeman et al., 2012).”

What the sources say

• Not checked yetcites Wakeman et al., 2012 source

In the paper

“For example, induction of ferritin H chain (FtH) expression in host tissues confers tolerance to malaria through FtH-mediated iron sequestration, ferroxidase activity, and inhibition of oxidative damage by modulation of JNK signaling (Gozzelino et al., 2012).”

What the sources say

• Not checked yetcites Gozzelino et al., 2012 source

In the paper

“Furthermore, iron serves as an important signal for some fungi during the transition from a commensal lifestyle to that of an invasive pathogen (Chen et al., 2011).”

What the sources say

• Not checked yetcites Chen et al., 2011 source

In the paper

“Accordingly, HO-1 induction limits the morbidity of experimental malaria (Seixas et al., 2009).”

What the sources say

• Not checked yetcites Seixas et al., 2009 source

In the paper

“The importance of hemozoin-mediated heme detoxification in P. falciparum is illustrated by the clinical efficacy of quinoline drugs, which inhibit hemozoin synthesis.”

In the paper

“Ingested hemoglobin is subsequently digested by a cascade of proteases before use as a nutrient source (Williamson et al., 2004).”

What the sources say

• Not checked yetcites Williamson et al., 2004 source

In the paper

“Both C. albicans and C. neoformans require reductive iron uptake for full virulence in animal infection models (Nevitt, 2011).”

What the sources say

• Not checked yetcites Nevitt, 2011 source

In the paper

“Yet other host iron-sequestering responses may fortify innate immunity.”

In the paper

“However, unlike bacterial pathogens, fungi can also produce intracellular siderophores for distribution and storage of iron.”

In the paper

“Thus, induction of host iron detoxification systems by one pathogen may alter susceptibility to another.”

In the paper

“The growth of C. neoformans, C. albicans, and H. capsulatum in iron-deplete media is enhanced upon addition of heme or hemoglobin (Foster, 2002; Hu et al., 2013; Weissman et al., 2002).”

What the sources say

• Not checked yetcites Foster, 2002 source
• Not checked yetcites Hu et al., 2013
• Not checked yetcites Weissman et al., 2002 source

In the paper

“Detoxification of iron and iron-containing compounds serves a cytoprotective role during infection by limiting the tissue damage associated with iron overload.”

In the paper

“However, HO-1 induction during experimental malaria impairs resistance to NTS by limiting the oxidative burst of granulocytes. (Cunnington et al., 2012).”

What the sources say

• Not checked yetcites Cunnington et al., 2012 source

In the paper

“Unlike bacterial heme uptake systems, hemoglobin uptake by C. albicans appears to utilize a novel endocytosis-mediated mechanism (Weissman et al., 2008).”

What the sources say

• Not checked yetcites Weissman et al., 2008 source

In the paper

“Similar to bacterial pathogens, a variety of pathogenic fungi produce siderophores, including the agents of endemic mycoses (Histoplasma capsulatum and Blastomyces dermatitidis), zygomycetic organisms (Rhizopus spp.), and other invasive molds (Aspergillus spp.) (Howard, 1999).”

What the sources say

• Not checked yetcites Howard, 1999 source

In the paper

“To counteract Mtb iron acquisition, IFN-gamma activates macrophages to downregulate cell-surface transferrin receptors, effectively decreasing iron concentrations in late endosomes (Olakanmi et al., 2002).”

What the sources say

• Not checked yetcites Olakanmi et al., 2002 source

In the paper

“In response to infection, the innate immune system further strengthens iron-withholding defenses, ensuring that the host-pathogen interface remains an ever-evolving battleground for precious metal.”

In the paper

“In summary, human pathogens have evolved a plethora of mechanisms to obtain host iron.”

In the paper

“but these compounds illustrate that an enhanced understanding of microbial iron acquisition strategies can further our understanding of human physiology.”

In the paper

“The recent termination of human clinical trials for a S. aureus IsdB-containing vaccine highlights that protective immunity in animal models of infection may not always correlate to vaccine efficacy in humans (Daum and Spellberg, 2012).”

What the sources say

• Not checked yetcites Daum and Spellberg, 2012 source

In the paper

“Vaccination with a mutated form of Na-APR-1 significantly reduced parasite burden in experimentally-infected canines (Pearson et al., 2009).”

What the sources say

• Not checked yetcites Pearson et al., 2009 source

In the paper

“Finally, the discovery of putative mammalian siderophores suggests that humans might use mechanisms analogous to microbes to maintain iron homeostasis (Bao et al., 2010; Devireddy et al., 2010).”

What the sources say

• Not checked yetcites Bao et al., 2010 source
• Not checked yetcites Devireddy et al., 2010 source

In the paper

“A “reverse vaccinology” approach revealed that antibodies targeting IsdA and IsdB were protective against S. aureus infection (Stranger-Jones et al., 2006).”

What the sources say

• Not checked yetcites Stranger-Jones et al., 2006 source

In the paper

“Similarly, Alteri et al. used a large-scale vaccinology approach to identify candidate uropathogenic E. coli vaccine antigens and found that immunization with six outer membrane iron receptors protected against UTI (Alteri et al., 2009).”

What the sources say

• Not checked yetcites Alteri et al., 2009 source