A battle for iron: host sequestration and Staphylococcus aureus acquisition

Probably not a substantial claim: may not pass S3 (load-bearing).

After leaving its colonization site, S. aureus can infect almost any human tissue.

“upon breaching this initial site of colonization, S. aureus has the capacity to infect nearly every tissue in the human body.”

• cites [2] David, 2010, Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic, Clin. Microbiol. Rev. sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

Vertebrates have developed complex systems to sequester iron, and pathogenic bacteria have developed equally complex systems to acquire it.

“To combat infection vertebrates have evolved sophisticated iron sequestration systems against which, pathogenic bacteria have concomitantly evolved equally elaborate iron acquisition mechanisms.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

S. aureus is the most common cause of hospital-acquired infections in the United States, and the proportion caused by MRSA is rising sharply.

“S. aureus is the most frequent cause of nosocomial infections in the United States, with the percentage of infections caused by methicillin resistant Staphylococcus aureus (MRSA) growing precipitously [3].”

• cites [3] Todd, 2006, Beyond MRSA: VISA and VRSA: what will ward off these pathogens in health care facilities?, Am. J. Nurs. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

S. aureus colonizes the anterior nares of about 30% of people.

“Staphylococcus aureus is a Gram-positive coccoid bacterium that innocuously colonizes the anterior nares of approximately 30% of the human population [1].”

• cites [1] Kuehnert, 2006, Prevalence of Staphylococcus aureus nasal colonization in the United States, 2001-2002, J. Infect. Dis. sourceNot checked yet

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Classified as probably not a substantial claim.

Most organisms, including disease-causing bacteria, need iron to live and multiply.

“Consequently most living organisms, including pathogenic bacteria, require iron to survive and replicate.”

Probably not a substantial claim: may not pass S3 (load-bearing).

S. aureus causes illnesses ranging from superficial wound infections to severe septicemia, toxic shock syndrome, and endocarditis.

“S. aureus can cause a spectrum of ailments ranging from superficial wound infections to more severe diseases such as septicemia, toxic shock syndrome and endocarditis [2].”

• cites [2] David, 2010, Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic, Clin. Microbiol. Rev. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Iron overload in thalassaemia has been implicated as a cause of the increased infections in this population.

“Iron overload associated with thalassaemia patients has been implicated as a cause for the increased infections within this population [18].”

• cites [18] Rahav, 2006, Severe infections in thalassaemic patients: prevalence and predisposing factors, Br. J. Haematol. sourceNot checked yet

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Iron overload in hereditary hemochromatosis impairs phagocytes by reducing chemotaxis and making it easier for engulfed bacteria to multiply inside macrophages.

“iron overload compromises the efficacy of phagocytic cells by decreasing their chemotactic capabilities and increasing the ease with which engulfed bacteria can proliferate intracellularly within macrophages [15].”

• cites [15] Khan, 2007, Association of hemochromatosis with infectious diseases: expanding spectrum, Int. J. Infect. Dis. sourceNot checked yet

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Hemopexin scavenges circulating heme and delivers it to the liver through receptor-mediated endocytosis.

“Hemopexin binds free heme and delivers it to the liver where it can be taken up by hepatic parenchymal cells through receptor-mediated endocytosis (Fig. 1) [13].”

• cites [13] Tolosano, 2010, Heme scavenging and the other facets of hemopexin, Antioxid. Redox Sign. sourceNot checked yet

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Iron starvation or fur inactivation significantly reduces TCA cycle enzymes and increases glycolytic proteins in S. aureus.

“either iron starvation or fur inactivation leads to a significant reduction in the abundance of numerous enzymes of the TCA cycle and a simultaneous increase in the abundance of proteins within the glycolytic pathway [19].”

• cites [19] Friedman, 2006, Staphylococcus aureus redirects central metabolism to increase iron availability, PLoS Pathog. sourceNot checked yet

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Shifting to fermentative metabolism benefits iron-starved S. aureus by increasing lactate production, lowering pH, and raising local free iron.

“Therefore, shifting to fermentative metabolism benefits iron starved S. aureus by increasing lactate production which decreases the surrounding pH and increases the local levels of free iron.”

May combine two claims.

Increased transferrin saturation reduces the bacteriostatic property of serum, and hereditary hemochromatosis is associated with higher risk of bacterial and viral infections.

“This increase in transferrin saturation decreases the bacteriostatic nature of serum as it is easier for pathogens to attain iron from transferrin [15]. Consequently HH is associated with an increased risk of both bacterial and viral infections [15].”

• cites [15] Khan, 2007, Association of hemochromatosis with infectious diseases: expanding spectrum, Int. J. Infect. Dis. sourceNot checked yet

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S. aureus IsdB binds human hemoglobin more efficiently than hemoglobin from other animal species, with a KD of 5.5 × 10−8 for human hemoglobin versus 9.8 × 10−7 for mouse hemoglobin.

“the S. aureus hemoglobin receptor IsdB binds human hemoglobin more efficiently than hemoglobin from other animal species [47]. In fact the KD of the interaction between recombinant IsdB and human hemoglobin is 5.5 × 10−8 as compared to a KD of 9.8 × 10−7 for the interaction between IsdB and mouse hemoglobin.”

• cites [47] Pishchany, 2010, Specificity for human hemoglobin enhances Staphylococcus aureus infection, Cell Host Microbe sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Iron overload in β thalassaemia occurs because dysfunctional erythropoiesis increases iron demand.

“Iron overload occurs in β thalassaemia due to the increased iron demand caused by dysfunctional erythropoiesis [16].”

• cites [16] Gardenghi, 2010, Hepcidin and Hfe in iron overload in beta-thalassemia, Ann. N. Y. Acad. Sci. sourceNot checked yet

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Δfur mutants and wildtype S. aureus grown in iron-deplete media produce markedly more lactate than wildtype grown in iron-replete conditions, lowering local pH.

“both Δfur mutants and wildtype S. aureus grown in iron-deplete media produce markedly more lactate than wildtype bacteria grown in iron-replete conditions, leading to a decrease in the local pH [19].”

• cites [19] Friedman, 2006, Staphylococcus aureus redirects central metabolism to increase iron availability, PLoS Pathog. sourceNot checked yet

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Transgenic mice expressing human hemoglobin are more susceptible to S. aureus infection than wildtype mice, demonstrating pathophysiological relevance.

“Transgenic mice that express human hemoglobin are more susceptible to S. aureus infection than wildtype mice demonstrating the pathophysiological relevance of these findings.”

• cites [47] Pishchany, 2010, Specificity for human hemoglobin enhances Staphylococcus aureus infection, Cell Host Microbe sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

Most human iron is heme, a tetrapyrrole ring with coordinated iron, usually bound by hemoproteins, most abundantly hemoglobin.

“The overwhelming majority of iron within humans is found in the form of heme; a tetrapyrrole ring with a coordinated iron center. Heme is often bound by hemoproteins, the most abundant of which is hemoglobin.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Infections are a major cause of death in thalassaemia patients, accounting for 12-46% of mortality.

“Infections are among the major causes of mortality in patients with thalassaemia (12–46%) along with cardiovascular disease and liver failure [18].”

• cites [18] Rahav, 2006, Severe infections in thalassaemic patients: prevalence and predisposing factors, Br. J. Haematol. sourceNot checked yet

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May combine two claims.

Hepcidin binding to ferroportin causes ferroportin endocytosis and degradation, reducing iron release into plasma.

“Upon binding to ferroportin, hepcidin causes ferroportin endocytosis and subsequent proteolytic degradation decreasing the release of iron into the plasma [12].”

• cites [12] Ganz, 2011, Hepcidin and iron regulation, 10 years later, Blood sourceNot checked yet

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S. aureus binds haptoglobin-hemoglobin complexes in vitro, suggesting it uses this complex as a nutrient iron source.

“S. aureus binds haptoglobin-hemoglobin complexes in vitro, suggesting that this protein complex is exploited as a source of nutrient iron [8].”

• cites [8] Dryla, 2003, Identification of a novel iron regulated staphylococcal surface protein with haptoglobin-haemoglobin binding activity, Mol. Microbiol. sourceNot checked yet

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The Isd system includes cell wall anchored heme binding proteins IsdA and IsdC, hemoglobin receptor IsdB, hemoglobin-haptoglobin receptor IsdH, membrane transporter IsdEF, and cytoplasmic heme oxygenases IsdG and IsdI.

“One such system is the iron regulated surface determinant (Isd) system which includes the cell wall anchored heme binding proteins (IsdA and IsdC), a hemoglobin receptor (IsdB), a hemoglobin-haptoglobin receptor (IsdH), a membrane transporter (IsdEF), and two cytoplasmic heme oxygenases (IsdG and IsdI) [22].”

• cites [22] Grigg, 2010, Structural biology of heme binding in the Staphylococcus aureus Isd system, J. Inorg. Biochem. sourceNot checked yet

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Hemopexin levels rise during inflammation and counteract the hemolytic activity of pathogenic bacteria.

“As an acute-phase protein, hemopexin concentrations increase during inflammation and are regulated by the cytokines IL-6, IL-11 IL-1β, leukemia inhibitory factor, and tumor necrosis factor (TNF)-α [14]. The increase in hemopexin levels during infection counteracts the hemolytic activity of pathogenic bacteria.”

• cites [14] Tolosano, 2002, Hemopexin: structure, function, and regulation, DNA Cell Biol. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

β thalassaemia is an inherited hemoglobin synthesis disorder caused by β globin mutations, leading to defective β chain production, ineffective erythropoiesis, abnormal α/β chain ratios, iron overload, and anemia.

“β Thalassaemia is an inherited disorder affecting hemoglobin synthesis. Mutations within the β globin gene cause diverse degrees of defective β chain production, ineffective erythropoiesis, improper α/βchain ratios, iron overload, and a range of anemia [16].”

• cites [16] Gardenghi, 2010, Hepcidin and Hfe in iron overload in beta-thalassemia, Ann. N. Y. Acad. Sci. sourceNot checked yet

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May combine two claims.

Lactoferrin binds free iron in lymph and mucosal secretions and is abundant in phagocytes, limiting intracellular iron for engulfed pathogens.

“Iron levels are also limited in lymph and mucosal secretions through lactoferrin, which quickly binds all free iron. Additionally, lactoferrin is a major component within phagocytes, ensuring that engulfed pathogens have limited access to intracellular iron.”

• cites [5] Bullen, 2005, Iron and infection: the heart of the matter, FEMS Immunol, Med. Microbiol.Not checked yet

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In the presence of iron, Fur binds a fur box upstream of iron-regulated genes and usually represses their transcription; iron starvation relieves this repression and activates transcription.

“In the presence of iron, Fur binds a consensus DNA sequence referred to as a fur box located upstream of the transcriptional start site of iron-regulated genes. The binding of Fur to the fur box typically inhibits the transcription of target genes. During conditions of iron starvation, Fur repression is alleviated and transcription is activated.”

• cites [19] Friedman, 2006, Staphylococcus aureus redirects central metabolism to increase iron availability, PLoS Pathog. sourceNot checked yet

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May combine two claims.

More than 90% of human iron is inside cells, making it unavailable to extracellular pathogens unless they can liberate it.

“greater than 90% of iron within the human body is located intracellularly making it inaccessible to extracellular pathogens unless mechanisms are employed to liberate these rich sources of nutrient iron.”

May combine two claims.

In a murine pneumonia model, fur mutants induce greater neutrophil recruitment despite reduced colonization and proliferation, and they can still proliferate in neutropenic mice, suggesting Fur controls an anti-neutrophil response that protects S. aureus in the lung.

“In a murine model of pneumonia, S. aureus fur mutants induce greater neutrophil recruitment despite a decreased ability to colonize and proliferate within the lung. Interestingly, S. aureus fur mutants are still able to proliferate in the lungs of neutropenic mice suggesting that Fur controls an anti-neutrophil response that protects S. aureus during infection of the vertebrate lung [21].”

• cites [21] Torres, 2010, Staphylococcus aureus Fur regulates the expression of virulence factors that contribute to the pathogenesis of pneumonia, Infect. Immun. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

In the United States, S. aureus causes more deaths than HIV.

“within the United States S. aureus is responsible for more deaths than HIV [4].”

• cites [4] CDC, 2007, HIV/AIDS Surveill. Rep.Not checked yet

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Classified as probably not a substantial claim.

Iron is needed by nearly all organisms, including S. aureus.

“Iron is required by nearly all living organisms and S. aureus is no exception.”

May combine two claims.

Inflammation-induced IL-6 and LPS-TLR4 signaling raise circulating hepcidin, which reduces available iron and prevents bacterial replication.

“induction of IL-6 production and LPS-mediated TLR4 signaling both cause increases in circulating hepcidin (Fig. 1) [12]. Inflammation-induced increases in hepcidin represent a hypoferremic response to infection which allows the host to respond to bacterial assault by further reducing available iron and preventing bacterial replication [12].”

• cites [12] Ganz, 2011, Hepcidin and iron regulation, 10 years later, Blood sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The SsrA tag is an eleven-amino-acid tag added to the carboxy-terminus of incompletely translated proteins and marks them for degradation.

“The N-end rule relates the half-life of a protein to the N-terminal amino acid while the SsrA tag is an eleven amino acid tag that is added to the carboxy-terminus of incompletely translated proteins relegating them to degradation [54–55].”

• cites [55] Keiler, 1996, Role of a peptide tagging system in degradation of proteins synthesized from damaged messenger RNA, Science sourceNot checked yet

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May combine two claims.

Both IsdG and IsdI bind and degrade heme.

“While both enzymes bind and degrade heme they are differentially regulated indicating a possible rationale for encoding two paralogous heme oxygenases [46, 51].”

• cites [46] Skaar, 2004, IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus, J. Biol. Chem. sourceNot checked yet

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• cites [51] Reniere, 2008, Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem, Mol. Microbiol. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Structural differences may keep S. lugdunensis IsdG from being targeted for degradation.

“This indicates that structural differences may exist in S. lugdunensis IsdG that prevent it from being targeted for degradation.”

May combine two claims.

S. lugdunensis IsdG and S. aureus IsdG are 68% identical in amino acid sequence, but the S. lugdunensis enzyme remains stable without heme.

“Although S. lugdunensis IsdG and S. aureus IsdG are 68% identical at the amino acid level the S. lugdunensis enzyme is stable in the absence of heme.”

• cites [50] Haley, 2011, Staphylococcus lugdunensis IsdG liberates iron from host heme, J. Bacteriol. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Acyldepsipeptides have antimicrobial activity by making cytoplasmic proteases constitutively active.

“This fact is underscored by the antimicrobial activity of acyldepsipeptides which render cytoplasmic proteases constitutively active [52].”

• cites [52] Brotz-Oesterhelt, 2005, Dysregulation of bacterial proteolytic machinery by a new class of antibiotics, Nat. Med. sourceNot checked yet

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Host tissues probably differ in accessible iron, so S. aureus may differ in how much it depends on heme iron.

“Different host tissues likely have varying amounts of accessible iron and therefore S. aureus may vary in its dependency on iron from heme.”

May combine two claims.

S. lugdunensis has a single IsdG-family heme oxygenase that is iron regulated.

“S. lugdunensis encodes a single IsdG-family heme oxygenase which is iron regulated.”

• cites [50] Haley, 2011, Staphylococcus lugdunensis IsdG liberates iron from host heme, J. Bacteriol. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

IsdG-family heme oxygenases have been characterized in S. lugdunensis, Bacillus anthracis, Bradyrhizobium japonicum, Brucella melitensis, and Mycobacterium tuberculosis.

“IsdG-family heme oxygenases have been characterized in S. lugdunensis, Bacillus anthracis, Bradyrhizobium japonicum, Brucella melitensis, and Mycobacterium tuberculosis [46, 50, 56–58].”

• cites [46] Skaar, 2004, IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus, J. Biol. Chem. sourceNot checked yet

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• cites [50] Haley, 2011, Staphylococcus lugdunensis IsdG liberates iron from host heme, J. Bacteriol. sourceNot checked yet

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• cites [56] Chim, 2010, Unusual diheme conformation of the heme-degrading protein from Mycobacterium tuberculosis, J. Mol. Biol. sourceNot checked yet

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• cites [57] Puri, 2006, The hmuQ and hmuD genes from Bradyrhizobium japonicum encode heme-degrading enzymes, J. Bacteriol. sourceNot checked yet

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• cites [58] Skaar, 2006, Bacillus anthracis IsdG, a heme-degrading monooxygenase, J. Bacteriol. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The product of MhuD heme degradation is unknown, so it is unclear whether its diheme active site makes staphylobilin.

“This unusual diheme conformation does not affect the heme degrading capabilities of MhuD, however, as the product of MhuD heme degradation has not been determined; it is unclear if the diheme active site degrades heme to staphylobilin.”

• cites [56] Chim, 2010, Unusual diheme conformation of the heme-degrading protein from Mycobacterium tuberculosis, J. Mol. Biol. sourceNot checked yet

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May combine two claims.

Both IsdG and IsdI are needed for full S. aureus virulence, and they are not functionally redundant during vertebrate infection.

“Taken together these data suggest that while both IsdG and IsdI are required for full virulence in S. aureus, and these enzymes are not functionally redundant during vertebrate infection [51].”

• cites [51] Reniere, 2008, Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem, Mol. Microbiol. sourceNot checked yet

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IsdG orthologs from these bacteria bind and degrade heme, but they differ in other respects.

“While IsdG orthologs from each of these bacteria have been shown to bind and degrade heme, differences do exist.”

• cites [46] Skaar, 2004, IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus, J. Biol. Chem. sourceNot checked yet

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• cites [50] Haley, 2011, Staphylococcus lugdunensis IsdG liberates iron from host heme, J. Bacteriol. sourceNot checked yet

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• cites [56] Chim, 2010, Unusual diheme conformation of the heme-degrading protein from Mycobacterium tuberculosis, J. Mol. Biol. sourceNot checked yet

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• cites [57] Puri, 2006, The hmuQ and hmuD genes from Bradyrhizobium japonicum encode heme-degrading enzymes, J. Bacteriol. sourceNot checked yet

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• cites [58] Skaar, 2006, Bacillus anthracis IsdG, a heme-degrading monooxygenase, J. Bacteriol. sourceNot checked yet

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May combine two claims.

Transcript levels of both isdG and isdI rise under iron-deplete conditions and are controlled by Fur.

“Both isdG and isdI transcript levels increase in iron-deplete conditions and are subjected to Fur-mediated regulation [51].”

• cites [51] Reniere, 2008, Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem, Mol. Microbiol. sourceNot checked yet

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May combine two claims.

IsdG degradation without heme does not proceed through the N-end rule or the SsrA tag, because neither terminus is required for proteolytic recognition.

“The targeted degradation of IsdG in the absence of heme does not occur through either the N-end rule or the SsrA tag as neither termini are required for proteolytic recognition [53].”

• cites [53] Reniere, 2011, The flexible loop of Staphylococcus aureus IsdG is required for its degradation in the absence of heme, Biochemistry sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The N-end rule and the SsrA tag are the best characterized mechanisms by which bacterial proteases recognize substrates.

“Currently, the most well characterized mechanisms for substrate recognition by bacterial proteases are the N-end rule and the SsrA tag.”

• cites [54] Varshavsky, 1996, The N-end rule: functions, mysteries, uses, Proc. Natl. Acad. Sci. U S A sourceNot checked yet

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• cites [55] Keiler, 1996, Role of a peptide tagging system in degradation of proteins synthesized from damaged messenger RNA, Science sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The N-end rule ties a protein's half-life to its N-terminal amino acid.

“The N-end rule relates the half-life of a protein to the N-terminal amino acid while the SsrA tag is an eleven amino acid tag that is added to the carboxy-terminus of incompletely translated proteins relegating them to degradation [54–55].”

• cites [54] Varshavsky, 1996, The N-end rule: functions, mysteries, uses, Proc. Natl. Acad. Sci. U S A sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Each MhuD monomer from M. tuberculosis binds two heme molecules, with the porphyrin rings stacked 3.45 Å apart.

“Each MhuD monomer binds two heme molecules with the porphyrin rings stacked 3.45 Å apart [56].”

• cites [56] Chim, 2010, Unusual diheme conformation of the heme-degrading protein from Mycobacterium tuberculosis, J. Mol. Biol. sourceNot checked yet

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May combine two claims.

No known staphylococcal protease degrades apo-IsdG, suggesting that S. aureus has an unidentified protease for protein turnover.

“Furthermore, none of the known staphylococcal proteases are responsible for the degradation of apo-IsdG, suggesting that S. aureus encodes an as-yet unidentified protease involved in protein turnover [53].”

• cites [53] Reniere, 2011, The flexible loop of Staphylococcus aureus IsdG is required for its degradation in the absence of heme, Biochemistry sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Some bacteria that contain IsdG are extremophiles living in very harsh environments.

“In fact, some of these IsdG-containing bacteria are considered extremophiles, occupying some of the earth's harshest environments.”

• cites [50] Haley, 2011, Staphylococcus lugdunensis IsdG liberates iron from host heme, J. Bacteriol. sourceNot checked yet

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May combine two claims.

Both ΔisdG and ΔisdI are attenuated in murine hearts, but only ΔisdG is attenuated in murine kidneys.

“Interestingly, while both S. aureus ΔisdG and S. aureus ΔisdI are attenuated for virulence in murine hearts, only S. aureus ΔisdG is attenuated for virulence within murine kidneys.”

• cites [51] Reniere, 2008, Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem, Mol. Microbiol. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Staphyloferrin A contributes to transferrin-iron acquisition by staphylococci but is not the main way S. aureus obtains iron from transferrin.

“Together this suggests that staphyloferrin A contributes to staphylococcal transferrin-iron acquisition but is not the predominant means by which S. aureus procures iron from transferrin.”

May combine two claims.

Orthologous HrtAB systems occur in several Gram-positive species, indicating that alleviating heme toxicity is a common challenge for many Gram-positive bacteria.

“Orthologous HrtAB systems have been identified in a number of species including L. monocytogenes, Bacillus thuringiensis,Bacillus cereus, Lactococcus lactis, Streptococcus agalactiae and S. epidermidis indicating that alleviation of heme toxicity is a common obstacle faced by many Gram positive bacteria [63, 66–67].”

• cites [63] Torres, 2007, A Staphylococcus aureus regulatory system that responds to host heme and modulates virulence, Cell Host Microbe sourceNot checked yet

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• cites [66] Pedersen, 2008, Impact of aeration and heme-activated respiration on Lactococcus lactis gene expression: identification of a heme-responsive operon, J. Bacteriol. sourceNot checked yet

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• cites [67] Fernandez, 2010, Two coregulated efflux transporters modulate intracellular heme and protoporphyrin IX availability in Streptococcus agalactiae, PLoS Pathog. sourceNot checked yet

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May combine two claims.

Both HssR and HssS are needed for heme adaptation, and inactivating either one causes hyper-susceptibility to lethal heme.

“Both HssR and HssS are required for heme adaptation and inactivating either hssR or hssS results in hyper-susceptibility to the lethal effects of heme.”

• cites [64] Stauff, 2007, Signaling and DNA-binding activities of the Staphylococcus aureus HssR-HssS two-component system required for heme sensing, J. Biol. Chem. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

HssRS is a two-component system made of the histidine kinase HssS and the response regulator HssR.

“Like NreBC, HssRS is a paradigmatic two component system consisting of a histidine kinase (HssS) and a response regulator (HssR) [64].”

• cites [64] Stauff, 2007, Signaling and DNA-binding activities of the Staphylococcus aureus HssR-HssS two-component system required for heme sensing, J. Biol. Chem. sourceNot checked yet

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May combine two claims.

Siderophore production in S. aureus is Fur-regulated and rises when the bacteria face iron stress.

“Siderophore production is Fur-regulated and consequently increases when the bacteria experience iron stress [19, 60].”

• cites [19] Friedman, 2006, Staphylococcus aureus redirects central metabolism to increase iron availability, PLoS Pathog. sourceNot checked yet

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• cites [60] Lindsay, 1994, Staphylococcal iron requirements, siderophore production, and iron-regulated protein expression, Infect. Immun. sourceNot checked yet

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May combine two claims.

IsdB is surface exposed and important during infection, making it a viable vaccine candidate.

“The hemoglobin binding protein IsdB plays a pivotal role during infection and is surface exposed establishing this protein as a viable vaccine candidate [47].”

• cites [47] Pishchany, 2010, Specificity for human hemoglobin enhances Staphylococcus aureus infection, Cell Host Microbe sourceNot checked yet

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May combine two claims.

The protective effect of IsdB vaccination is probably due to anti-IsdB antibodies, because mice with higher anti-IsdB titers were more likely to survive.

“The protective effect of the vaccine is likely due to the production of anti-IsdB antibodies as mice with higher anti-IsdB titers had a greater probability of surviving than those with low anti-IsdB titers [68].”

• cites [68] Kuklin, 2006, A novel Staphylococcus aureus vaccine: iron surface determinant B induces rapid antibody responses in rhesus macaques and specific increased survival in a murine S. aureus sepsis model, Infect. Immun. sourceNot checked yet

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May combine two claims.

After binding iron, staphyloferrin A and staphyloferrin B are imported into the cytoplasm by HtsABC and SirABC, respectively.

“Upon binding iron, both staphyloferrin A and staphyloferrin B are transported into the cytoplasm through the ABC transporters HtsABC and the staphylococcal iron regulated transporter (SirABC), respectively [61].”

• cites [61] Beasley, 2010, Siderophore-mediated iron acquisition in the staphylococci, J. Inorg. Biochem. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The HrtAB system is made of the ATPase HrtA and the permease HrtB.

“The HrtAB system is comprised of an ATPase (HrtA) and a permease (HrtB).”

May combine two claims.

B. japonicum obtains heme from leghemoglobin inside plant nodules, and leghemoglobin can make up as much as 30% of soluble protein in those nodules.

“Within these nodules B. japonicum acquires heme from leghemoglobin, a plant hemoglobin with structural properties similar to animal hemoglobins that can comprise up to 30% of the total soluble protein within plant nodules [59].”

• cites [59] Noya, 1997, Heme compounds as iron sources for nonpathogenic Rhizobium bacteria, J. Bacteriol. sourceNot checked yet

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May combine two claims.

A S. aureus sbn mutant grows poorly in serum but reaches wild-type densities after long incubation, probably because it makes staphyloferrin A.

“A S. aureus sbn mutant strain has impaired growth in serum, but achieves wildtype cell densities after extensive incubation, presumably due to the production of staphyloferrin A [62].”

• cites [62] Beasley, 2009, Characterization of staphyloferrin A biosynthetic and transport mutants in Staphylococcus aureus, Mol. Microbiol. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The ABC-type transporter strongly induced by heme is called hrtAB.

“Since this ABC-type transporter is dramatically increased in response to heme it has been termed the heme regulated transporter (hrtAB) [19].”

• cites [19] Friedman, 2006, Staphylococcus aureus redirects central metabolism to increase iron availability, PLoS Pathog. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In some coagulase-negative staphylococci, the sfa locus is thought to be constitutively expressed.

“However, in some species of coagulase-negative staphylococci the sfa locus is believed to be constitutively expressed [60, 62].”

• cites [60] Lindsay, 1994, Staphylococcal iron requirements, siderophore production, and iron-regulated protein expression, Infect. Immun. sourceNot checked yet

  Not checked in the free run.

• cites [62] Beasley, 2009, Characterization of staphyloferrin A biosynthetic and transport mutants in Staphylococcus aureus, Mol. Microbiol. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Staphyloferrin B is structurally different from staphyloferrin A but is also a hydrophilic NIS siderophore.

“Staphyloferrin B is structurally distinct from staphyloferrin A but like staphyloferrin A is a hydrophilic NIS siderophore.”

• cites [61] Beasley, 2010, Siderophore-mediated iron acquisition in the staphylococci, J. Inorg. Biochem. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The sfa locus has four genes: the sfaABC operon and a divergently transcribed sfaD.

“The sfa locus contains four genes, the three gene operon sfaABC and a divergently transcribed sfaD [60, 62].”

• cites [60] Lindsay, 1994, Staphylococcal iron requirements, siderophore production, and iron-regulated protein expression, Infect. Immun. sourceNot checked yet

  Not checked in the free run.

• cites [62] Beasley, 2009, Characterization of staphyloferrin A biosynthetic and transport mutants in Staphylococcus aureus, Mol. Microbiol. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

HrtA ATPase activity is affected by ATP concentration, temperature, pH, and metal concentrations.

“The ATPase activity of HrtA is influenced by many cellular factors including ATP concentrations, temperature, pH, and metal concentrations [65].”

• cites [65] Stauff, 2008, Staphylococcus aureus HrtA is an ATPase required for protection against heme toxicity and prevention of a transcriptional heme stress response, J. Bacteriol. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Heme exposure causes HssS to autophosphorylate and then transphosphorylate HssR.

“Heme exposure leads to the autophosphorylation of HssS which subsequently transphosphorylates the response regulator HssR.”

• cites [64] Stauff, 2007, Signaling and DNA-binding activities of the Staphylococcus aureus HssR-HssS two-component system required for heme sensing, J. Biol. Chem. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The sbn locus contains the genes for staphyloferrin B synthesis and has a consensus Fur box in its operator region.

“The genes encoding the enzymatic machinery required for staphyloferrin B synthesis lie within the sbn locus which has a consensus fur box within the operator region for the operon [61].”

• cites [61] Beasley, 2010, Siderophore-mediated iron acquisition in the staphylococci, J. Inorg. Biochem. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

HtsBC transports heme into the cytoplasm, suggesting that HtsABC may act as a dual iron and heme transporter.

“Additionally, HtsBC has been found to transport heme into the cytoplasm suggesting that HtsABC may serve as a dual iron/heme transporter [37].”

• cites [37] Skaar, 2004, Iron-source preference of Staphylococcus aureus infections, Science sourceNot checked yet

  Not checked in the free run.

May combine two claims.

S. aureus makes two siderophores, staphyloferrin A and staphyloferrin B, both through the NIS pathway, and secretes them.

“S. aureus encodes for two siderophores, staphyloferrin A and staphyloferrin B, and both are synthesized through the NIS pathway and then secreted into the extracellular milieu.”

• cites [61] Beasley, 2010, Siderophore-mediated iron acquisition in the staphylococci, J. Inorg. Biochem. sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Pathogenic bacteria evolved multi-faceted iron acquisition systems to extract iron from host proteins and access intracellular iron pools.

“To circumvent the iron sequestration of the host, pathogenic bacteria have evolved multi-faceted iron acquisition systems to extract iron from host proteins and gain access to intracellular pools of iron.”

Classified as probably not a substantial claim.

Antibodies against IsdB may protect by blocking iron acquisition through the Isd system.

“This raises the interesting possibility that antibodies against IsdB provide protection by inhibiting iron acquisition through the Isd system.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Iron acquisition is a critical determinant of staphylococcal pathogenesis and is exploited by vertebrates through nutritional immunity.

“Iron acquisition is a critical determinant in staphylococcal pathogenesis and one that is exploited by vertebrates through nutritional immunity.”

May combine two claims.

Gram-positive bacteria are usually resistant to complement-mediated lysis, so clearance of S. aureus requires opsonophagocytic killing by immune cells.

“Gram-positive bacteria are typically resistant to complement mediated lysis, therefore host clearance of S. aureus requires opsonophagocytic killing by immune cells [69].”

• cites [69] Kim, 2010, IsdA and IsdB antibodies protect mice against Staphylococcus aureus abscess formation and lethal challenge, Vaccine sourceNot checked yet

  Not checked in the free run.