Staphylococcus aureus Targets the Duffy Antigen Receptor for Chemokines (DARC) to Lyse Erythrocytes
Open accessAbstract
SUMMARY In order for Staphylococcus aureus to thrive inside the mammalian host, the bacterium has to overcome iron scarcity. S. aureus is thought to produce toxins that lyse erythrocytes, releasing hemoglobin, the most abundant iron source in mammals. Here we identify the Duffy antigen receptor for chemokines (DARC) as the receptor for the S. aureus hemolytic leukocidins LukED and HlgAB. By assessing human erythrocytes with DARC polymorphisms, we determined that HlgAB and LukED-mediated lysis directly relates to DARC expression. DARC is required for S. aureus-mediated lysis of human erythrocytes and DARC overexpression is sufficient to render cells susceptible to toxin-mediated lysis. HlgA and LukE bind directly to DARC through different regions, and by targeting DARC, HlgAB and LukED support S. aureus growth in a hemoglobin acquisition-dependent manner. These findings elucidate how S. aureus targets and lyses erythrocytes to release one of the scarcest nutrients within the mammalian host.
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- Findingown data
CXCL8 completely antagonizes LukED-induced hemolysis irrespective of buffer conditions.
“Pre-treatment of erythrocytes with the DARC ligand CXCL8 (or IL-8) modestly shifted the EC50 for HlgAB (1.14 to 8.58 nM), while it completely antagonized hemolysis induced by LukED irrespective of buffer conditions (Figure 3C and S3A).”
Quote in the paperSubstantial claim - Findingown data
The EC50 of HlgAB and LukED directly correlates with the total number of DARC receptors on the erythrocyte surface.
“Half-maximal effective concentration (EC50) of the toxins directly correlated with the total number of receptors on the erythrocyte surface (Figure 1D and 1F).”
Quote in the paperSubstantial claim - Findingown data
The difference in susceptibility to HlgAB and LukED between donors is specifically related to erythroid DARC expression.
“The difference in susceptibility to HlgAB and LukED between donors was specifically related to erythroid expression levels of DARC, as levels of CD55 (also known as DAF) were equal in all donors (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
Among the β-barrel pore-forming toxins made by S. aureus, HlgAB and LukED are the most potent hemolytic leukocidins against human erythrocytes.
“Of the β-barrel pore-forming toxins produced by S. aureus, HlgAB and LukED are the most potent hemolytic leukocidins against human erythrocytes (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
CD55 levels were equal in all donors.
“The difference in susceptibility to HlgAB and LukED between donors was specifically related to erythroid expression levels of DARC, as levels of CD55 (also known as DAF) were equal in all donors (Figure 1B).”
Quote in the paperSubstantial claim
- Findingown data
CXCL8 significantly inhibits LukE binding to DARC when present at four-fold or greater concentration than LukE.
“In contrast, CXCL8 significantly inhibited LukE binding to DARC when the chemokine was present at four fold (1:0.25) or greater (1:0.125 and 1:0.0625) concentration than LukE (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
CXCL8 modestly shifts the EC50 for HlgAB from 1.14 to 8.58 nM.
“Pre-treatment of erythrocytes with the DARC ligand CXCL8 (or IL-8) modestly shifted the EC50 for HlgAB (1.14 to 8.58 nM), while it completely antagonized hemolysis induced by LukED irrespective of buffer conditions (Figure 3C and S3A).”
Quote in the paperSubstantial claim - Findingown data
LukE binds DARC with a KD of 56.4 nM.
“HlgA and LukE bound DARC with a KD of 29.2 nM and 56.4 nM, respectively (Figure 2A).”
Quote in the paperSubstantial claim - Findingown data
Mutation of N-terminal glycosylation sites N16A, N27A, or N33A moderately reduces susceptibility to HlgAB or LukED.
“Mutation of N-terminal glycosylation sites (N16A, N27A, or N33A) resulted in moderately reduced susceptibility of cells towards HlgAB or LukED (Figures 3A and 3B).”
Quote in the paperSubstantial claim - Findingown data
The hemolytic activity of HlgAB and LukED is increased in low pH conditions.
“Additional studies showed increased hemolytic activity in low pH conditions (Figure 2D).”
Quote in the paperNot a substantial claim - Findingcitation
The KD of HlgA for DARC is about 6-fold higher than for CXCR1.
“The KD-value of HlgA for DARC is approximately 6-fold higher compared to CXCR1, which serves as a neutrophil receptor for HlgA (Spaan et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Spaan et al., 2014 source
Not checked in the free run.
- Findingown data
Cells transfected with murine DARC are more susceptible to LukED than to HlgAB.
“In contrast to human DARC, we observed that cells transfected with murine DARC were more susceptible to LukED than to HlgAB (Figure S2A and S2B).”
Quote in the paperNot a substantial claim - Findingown data
There is no significant difference in bacterial burden between WT and Δhla-infected mice.
“The bacterial burden reduction observed with the Δhlg ΔlukED strain was specific, with no significant difference between the bacterial burden of WT and Δhla-infected mice, even though α-toxin exhibits hemolytic activity in vitro towards murine erythrocytes (Figure S2C).”
Quote in the paperSubstantial claim - Findingown data
DARC-negative erythrocytes with phenotype Fya−/b− and genotype FY*BES/FY*BES are fully resistant to HlgAB and LukED.
“Indeed, DARC-negative erythrocytes (phenotype Fya−/b− with genotype FY*BES/FY*BES) were fully resistant to HlgAB and LukED (Figure 1C and 1E).”
Quote in the paperSubstantial claim - Findingown data
Mutation D283A in ECL3 has the inverse effect of E202A on susceptibility to HlgAB and LukED.
“The inverse effect was observed with aspartic acid in ECL3 (D283A) (Figures 3A and 3B).”
Quote in the paperSubstantial claim - Findingown data
The hemolytic activity of both HlgAB and LukED is enhanced in saline (unbuffered) compared to buffer.
“We observed that the hemolytic activity of both HlgAB and LukED was enhanced in saline (unbuffered) compared to buffer (Figure 2C).”
Quote in the paperNot a substantial claim - Findingown data
Erythrocytes with intermediate or very low DARC expression show intermediate susceptibility to both HlgAB and LukED.
“individuals expressing intermediate (phenotype Fyb+weak/b+weak with genotype FY*X/*X) or very low levels of DARC (phenotype Fyb−/b+weak with genotype FY*BES/FY*X) (Figure 1B) showed intermediate susceptibility to both HlgAB and LukED (Figure 1C and 1E).”
Quote in the paperSubstantial claim - Findingown data
HlgA binds DARC with a KD of 29.2 nM.
“HlgA and LukE bound DARC with a KD of 29.2 nM and 56.4 nM, respectively (Figure 2A).”
Quote in the paperSubstantial claim - Findingown data
At least a 10-fold higher EC50 was observed for both HlgAB and LukED for DARC compared to CXCR1.
“Consistent with the obtained affinities, at least a 10-fold higher EC50 was observed for both HlgAB and LukED for DARC when compared to CXCR1 (Figure 2B).”
Quote in the paperNot a substantial claim - Findingcitation
The affinity of HlgA and LukE for DARC is lower than for their myeloid receptors CXCR1 and CXCR2.
“The affinity of the binding components HlgA and LukE for DARC is lower than their myeloid receptors, CXCR1 and CXCR2 (Reyes-Robles et al., 2013; Spaan et al., 2014).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingown data
HlgAB is sufficient for the observed erythrocyte lysis by S. aureus in the ex vivo experiment.
“Growth of isogenic strains revealed that HlgAB is sufficient for the observed erythrocyte lysis in this ex vivo experiment (Figure 4B) and this was recapitulated with different S. aureus strains (Figure S4B).”
Quote in the paperSubstantial claim - Findingown data
A monoclonal antibody against DARC (Fya) does not protect against HlgAB or LukED.
“In contrast to CXCL8, a commercially available monoclonal against DARC (Fya) did not confer protection to HlgAB or LukED (Figure S3B), nor did high concentrations of a nanobody targeting the DARC Fy6-epitope.”
Quote in the paperSubstantial claim - Findingown data
The ΔisdBH strain is significantly growth impaired compared to WT S. aureus in medium supplemented with cell-free extracts from toxin-treated erythrocytes.
“In contrast to wild type (WT) S. aureus, the ΔisdBH strain was significantly growth impaired in medium supplemented with cell-free extracts from toxin treated erythrocytes (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
DARC-Fya and DARC-Fyb confer equal susceptibility to HlgAB and LukED in transfected HEK293T cells.
“DARC-Fya and -Fyb conferred equal susceptibility to these toxins (Figure 2B).”
Quote in the paperNot a substantial claim - Findingown data
CXCL8 does not affect HlgA binding to DARC.
“CXCL8 did not affect HlgA binding to DARC (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
HlgC binds DARC with a KD of 229.0 nM.
“Consistent with the limited hemolytic activity of HlgCB, the KD of HlgC for DARC was 229.0 nM (Figure 2A).”
Quote in the paperSubstantial claim - Findingown data
A nanobody targeting the DARC Fy6 epitope does not protect against HlgAB or LukED.
“In contrast to CXCL8, a commercially available monoclonal against DARC (Fya) did not confer protection to HlgAB or LukED (Figure S3B), nor did high concentrations of a nanobody targeting the DARC Fy6-epitope.”
Quote in the paperSubstantial claim - Findingown data
DARC is the erythroid receptor for both HlgAB and LukED, the main hemolytic leukocidins in S. aureus.
“Here, we identify the Duffy antigen receptor for chemokines (DARC) as the erythroid receptor for both HlgAB and LukED, the main hemolytic leukocidins in S. aureus.”
Quote in the paperSubstantial claim - Findingown data
The actual number of receptors on the cell surface dictates susceptibility to these hemolytic toxins.
“Consistent with this, our data suggests that the actual number of receptors on the cell surface dictates susceptibility to these hemolytic toxins.”
Quote in the paperSubstantial claim - Findingown data
A tyrosine in the N-terminus of DARC is essential for interaction with both HlgAB and LukED.
“Using alanine substitution mutants, we identified a tyrosine in the N-terminus of DARC that is essential for the interaction with both HlgAB and LukED and has been described as sulfated (Choe et al., 2005).”
Quote in the paperSubstantial claim - Findingcitation
An N-terminal cysteine (C51) involved in DARC interaction with LukED is also involved in binding CXCL8.
“An N-terminal cysteine (C51) identified as involved in the interaction of DARC with LukED is also involved in binding CXCL8 (Tournamille et al., 2003), supporting the notion that this chemokine directly blocks receptor binding by LukE.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tournamille et al., 2003 source
Not checked in the free run.
- Findingown data
HlgAB and LukED interact differentially with DARC.
“Otherwise, our data show that HlgAB and LukED interact differentially with DARC.”
Quote in the paperSubstantial claim - Findingnone given
The S. aureus strains investigated in this study all contain the genes encoding HlgAB and LukED.
“The S. aureus strains investigated in this study all contain the genes encoding HlgAB and LukED, thus demonstrating that S. aureus-mediated hemolysis requires DARC and these leukocidins.”
Quote in the paperSubstantial claim - Interpretationreasoning
HlgA determines erythroid specificity because HlgAB and HlgCB share HlgB but differ in hemolytic activity.
“The divergent activity of HlgAB and HlgCB, which share HlgB, indicates that HlgA drives erythroid specificity.”
Quote in the paperSubstantial claim - Interpretationreasoning
The restricted hemolytic activity of different but closely related bi-component toxins suggests they target specific cellular receptors.
“The restricted hemolytic activity of the different but closely related bi-component toxins suggests targeting of specific cellular receptors.”
Quote in the paperSubstantial claim - Interpretationcitation
The lack of a LukED contribution to ex vivo lysis is not surprising because LukED is produced at low levels in vitro.
“Notably, the lack of a LukED contribution is not surprising due to low production of this toxin in vitro (Alonzo et al., 2012; Gravet et al., 1998).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationown data
DARC targeting by HlgAB and LukED is dictated by different domains of the receptor.
“Together, these data demonstrate that DARC targeting by these toxins is dictated by different domains of the receptor.”
Quote in the paperSubstantial claim - Interpretationown data
The hemolytic activity of HlgAB and LukED depends on DARC.
“Taken together, these data demonstrate that the hemolytic activity of HlgAB and LukED is dependent on DARC.”
Quote in the paperSubstantial claim - Interpretationown data
Resistance of DARC-negative erythrocytes to P. vivax and P. knowlesi together with our findings supports the notion that this gene could undergo positive selection in response to different diseases caused by important human pathogens.
“However, the resistance of DARC negative erythrocytes to the parasites P. vivax and P. knowlesi together with our findings, further support the notion that this gene could undergo positive selection in response to different diseases caused by important human pathogens.”
Quote in the paperNot a substantial claim - Premisecitation
A substantial part of the human population carries a homozygous mutation in the erythroid-specific promoter of FY gene, resulting in lack of DARC expression on erythrocytes but not non-erythroid tissues.
“A substantial part of the human population carries a homozygous mutation (FY*AES or FY*BES alleles for erythrocyte silent) in the erythroid-specific promoter of the FY gene, resulting in a lack of expression of the receptor on erythrocytes (Fya−/b− phenotype) but not in non-erythroid tissues (Tournamille et al., 1995; Zimmerman et al., 1999).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
α-toxin has limited hemolytic activity towards human erythrocytes due to lack of its receptor ADAM10.
“Although a potent hemolysin on mouse, rabbit and sheep erythrocytes, α-toxin has limited hemolytic activity towards human erythrocytes (Hildebrand et al., 1991) due to the lack of its receptor, ADAM10 (Wilke and Bubeck Wardenburg, 2010).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Hildebrand et al., 1991 source
Not checked in the free run.
- cites Wilke and Bubeck Wardenburg, 2010
Not checked in the free run.
- Premisereasoning
The hemolytic activity of the toxins remains unexplained by the reported leukocyte receptors.
“Despite this, the hemolytic activity of the toxins remains unexplained by the reported leukocyte receptors.”
Quote in the paperSubstantial claim - Premisecitation
Approximately 80% of S. aureus strains carry the genes encoding LukED.
“Strictly following clonal lineage, approximately 80% of S. aureus strains carry the genes encoding LukED (McCarthy and Lindsay, 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites McCarthy and Lindsay, 2013
Not checked in the free run.
- Interpretationreasoning
The contribution of α-toxin, β-hemolysin, and PSMs to the release of iron from human erythrocytes seems unlikely.
“As such, the contribution of α-toxin, β-hemolysin, and PSMs to the release of iron from human erythrocytes seems unlikely.”
Quote in the paperSubstantial claim - Premisecitation
The genes encoding HlgAB are present in over 99.5% of human S. aureus isolates.
“The genes encoding HlgAB are present in over 99.5% of human S. aureus isolates (Prevost et al., 1995).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Prevost et al., 1995 source
Not checked in the free run.
- Premisecitation
IsdB exhibits low affinity for murine hemoglobin compared to human hemoglobin.
“One such factor is the staphylococcal hemoglobin receptor IsdB, which exhibits low affinity for murine hemoglobin as compared to human hemoglobin (Pishchany et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pishchany et al., 2010 source
Not checked in the free run.
- Interpretationcitation
CXCL8 directly blocks receptor binding by LukE.
“An N-terminal cysteine (C51) identified as involved in the interaction of DARC with LukED is also involved in binding CXCL8 (Tournamille et al., 2003), supporting the notion that this chemokine directly blocks receptor binding by LukE.”
Quote in the paperNot a substantial claim
- May combine two claims. 23
- Classified as probably not a substantial claim. 13
May combine two claims.
Findingown dataThe hemolytic activity of HlgAB and LukED is in the nanomolar range and is exclusively driven by DARC expression.
“Our data shows that the hemolytic activity of HlgAB and LukED is in the nanomolar range and is exclusively driven by DARC expression.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHlgCB and α-toxin cause only limited hemolysis of human erythrocytes, while PVL and LukAB are inactive against them.
“In contrast, HlgCB and α-toxin induce only limited hemolysis, while PVL and LukAB are inactive towards human erythrocytes (Figure 1A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataS. aureus induces hemolysis of erythrocytes in a time-, bacterial density-, and DARC-dependent manner.
“We observed that S. aureus induced hemolysis of erythrocytes in a time, bacterial density, and DARC-dependent manner (Figure 4A and Figures S4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMutation D58A+D59A causes partial resistance to HlgAB and enhanced susceptibility to LukED.
“While mutation of two adjacent aspartic acid residues (D58A+D59A) resulted in a partial resistance of cells to HlgAB, mutation of the same residues enhanced susceptibility to LukED (Figures 3A and 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPvDBP does not antagonize HlgAB cytotoxicity but minimally protects against LukED.
“Similarly, PvDBP did not antagonize cytotoxicity of HlgAB, while it minimally protected against LukED (Figure S3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMutation C51S strongly affects susceptibility to LukED but not HlgAB.
“Surprisingly, a disulfide bond-disrupting mutation (C51S) strongly affected susceptibility to LukED but not to HlgAB (Figures 3A and 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHlgAB and LukED each promote S. aureus growth in iron-starved medium supplemented with cell-free extracts of toxin-treated erythrocytes.
“We observed that HlgAB and LukED were each capable of promoting S. aureus growth (Figure 4C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMutation Y41A but not Y30A results in resistance to both HlgAB and LukED.
“Mutation of the second N-terminal tyrosine (Y41A) but not the first (Y30A) resulted in resistance to both HlgAB and LukED (Figures 3A and 3B), which is similar to what has been observed for PvDBP (Choe et al., 2005; Tournamille et al., 2005).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMutation P50A reduces susceptibility to both HlgAB and LukED.
“Mutation of a proline in close proximity to the first transmembrane region of the receptor (P50A) reduced susceptibility to both toxins (Figures 3A and 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMutation E202A in ECL2 slightly enhances susceptibility to HlgAB but reduces LukED cytotoxicity.
“Mutation of a glutamic acid in ECL2 (E202A) slightly enhanced susceptibility of cells to HlgAB, but reduced cytotoxicity of LukED.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn systemically infected mice, inactivation of lukED and hlgACB phenocopied deletion of hemoglobin receptors, causing 3-log and 4-log reductions in bacterial burden, respectively.
“Inactivation of lukED and hlgACB phenocopied the deletion of the hemoglobin receptors, resulting in a 3-log and 4-log reductionin bacterial burden, respectively (Figure 4D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPrimary murine erythrocytes are susceptible to both HlgAB and LukED.
“Consistent with the transfection data, primary murine erythrocytes were susceptible to both HlgAB and LukED (Figure S2B).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDARC is sufficient to render mammalian cells susceptible to HlgAB and LukED, and the toxins' hemolytic activity is likely influenced by the local environment of infected tissues.
“Collectively, these data indicate that DARC is sufficient to render mammalian cells susceptible to HlgAB and LukED, and that the hemolytic activity of these toxins is likely to be influenced by the local environment of infected tissues.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMurine DARC shares approximately 63% amino acid sequence homology with human DARC.
“Thus, we also evaluated if HlgAB and LukED can target murine DARC, which shares amino acid sequence homology of approximately 63% with human DARC (Luo et al., 1997).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Luo et al., 1997 source
Not checked in the free run.
May combine two claims.
Interpretationown dataS. aureus targets DARC to lyse erythrocytes in a HlgAB- and LukED-dependent manner to release hemoglobin, promoting bacterial replication.
“Altogether, these data suggest that S. aureus targets DARC to lyse erythrocytes in a HlgAB and LukED-dependent manner to release hemoglobin, promoting bacterial replication.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationFree iron is scarce in the host, an innate immune defense known as nutritional immunity.
“In the host, however, free iron is scarce, an innate immune defense strategy of the host known as “nutritional immunity” (Andrews et al., 2003; Schaible and Kaufmann, 2004; Weinberg, 1975).”
Quote in the paperSubstantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationHeme iron is S. aureus's preferred iron source during infection.
“Heme iron is S. aureus’s preferred iron source during infection (Skaar et al., 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Skaar et al., 2004
Not checked in the free run.
May combine two claims.
Premisecitationβ-hemolysin is an enzyme with sphingomyelinase activity; erythrocyte lysis by β-hemolysin is observed only after heat-cold shock incubation and in 90% of S. aureus isolates hlb is inactivated by bacteriophage integration.
“β-hemolysin (encoded by the hlb gene) is an enzyme with sphingomyelinase activity. Erythrocyte lysis by β-hemolysin is observed only after heat-cold shock incubation (Bernheimer et al., 1974) and in 90% of S. aureus isolates the hlb gene is inactivated by integration of β-hemolysin-converting bacteriophages (van Wamel et al., 2006).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe respective immune cell receptor counterparts of these leukocidins have been identified.
“The respective immune cell receptor counterparts of these leukocidins have been identified (Alonzo et al., 2013; DuMont et al., 2013; Reyes-Robles et al., 2013; Spaan et al., 2013a; Spaan et al., 2014).”
Quote in the paperNot a substantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationSeveral of the leukocidins also exhibit hemolytic activity.
“Interestingly, several of the leukocidins also exhibit hemolytic activity (Vandenesch et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vandenesch et al., 2012 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe current CA-MRSA epidemic in the United States and elsewhere disproportionally affects individuals of African descent with severe and invasive infections.
“The current epidemic of CA-MRSA in the United States and elsewhere disproportionally affects individuals of African descent with severe and invasive infections (Fridkin et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fridkin et al., 2005 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningHigh DARC expression and possibly lack of cellular membrane repair mechanisms make erythrocytes highly susceptible to the toxins.
“High expression levels of DARC and possibly lack of cellular membrane repair mechanisms make erythrocytes highly susceptible to the toxins.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe Duffy system discriminates two antigens (Fya and Fyb), based on a codon 42 polymorphism encoding glycine in FY*A and aspartic acid in FY*B.
“This system discriminates two antigens (Fya and Fyb), based on a codon 42 polymorphism encoding a glycine in approximately half of human alleles (FY*A) and an aspartic acid in the other half (FY*B) (Iwamoto et al., 1995).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Iwamoto et al., 1995 source
Not checked in the free run.
May combine two claims.
Interpretationown dataIn vivo studies revealed a remarkable similarity in phenotypes of isogenic mutants lacking either hemoglobin receptors or hemolytic leukocidins, suggesting these toxins contribute to nutrient acquisition during infection.
“Nevertheless, our in vivo studies revealed a remarkable similarity in the phenotypes of isogenic mutants lacking either the hemoglobin receptors or the hemolytic leukocidins, suggesting that these toxins contribute to nutrient acquisition during infection.”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse systemic infection model is informative for human S. aureus pathogenesis despite known species differences in virulence factor compatibility.
May combine two claims.
InterpretationreasoningS. aureus-mediated hemolysis requires DARC and these leukocidins.
“The S. aureus strains investigated in this study all contain the genes encoding HlgAB and LukED, thus demonstrating that S. aureus-mediated hemolysis requires DARC and these leukocidins.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationThe N-terminal tyrosine of DARC has been described as sulfated.
“Using alanine substitution mutants, we identified a tyrosine in the N-terminus of DARC that is essential for the interaction with both HlgAB and LukED and has been described as sulfated (Choe et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Choe et al., 2005 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.
InterpretationreasoningSocio-economic factors and other underlying diseases likely contribute to this predisposition, precluding epidemiological assessment of the contribution of erythroid DARC expression to S. aureus infection.
“Socio-economic factors and other underlying diseases likely contribute to this predisposition, precluding epidemiological assessment of the contribution of erythroid DARC expression to S. aureus infection.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOther rare mutations result in low-level expression of DARC (allele FY*X resulting in Fyb+weak phenotype).
“Other, yet rare, mutations result in low-level expression of DARC (allele FY*X resulting in Fyb+weak phenotype) (Tournamille et al., 1998).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tournamille et al., 1998 source
Not checked in the free run.
May combine two claims.
PremisecitationPSMs perforate lipid bilayer membranes in a receptor-independent manner and their cytotoxic activity is neutralized by serum lipoproteins.
“Phenol soluble modulins (PSMs), including δ-toxin, are small amphipathic peptides, which perforate lipid bilayer membranes in a receptor-independent manner (Wang et al., 2007). Cytotoxic activity of PSMs is neutralized by serum lipoproteins (Surewaard et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe bi-component pore-forming leukocidins are considered a pathogenic strategy to evade the cellular host immune response.
“The bi-component pore-forming leukocidins are considered a pathogenic strategy to evade the cellular host immune response (Alonzo and Torres, 2014; Spaan et al., 2013b).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Alonzo and Torres, 2014
Not checked in the free run.
- cites Spaan et al., 2013b
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationDARC is an atypical chemokine receptor and the antigen of the Duffy (Fy) blood group system.
“DARC is an atypical chemokine receptor and the antigen of the Duffy (Fy) blood group system (Tournamille et al., 1995; Tournamille et al., 1998; Wasniowska and Hadley, 1994).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataUsing DARC positive and negative erythrocytes, the study shows that S. aureus-induced hemolysis is strictly mediated by DARC and these leukocidins and that leukocidin-dependent hemolysis favors S. aureus growth.
“Using DARC positive and negative erythrocytes, we show that hemolysis induced by S. aureus is strictly mediated by DARC and these leukocidins and that leukocidin-dependent hemolysis favors S. aureus growth.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationIron is essential for proliferation and virulence of S. aureus.
“As with many pathogens (Schaible and Kaufmann, 2004), iron is essential for proliferation and virulence of S. aureus (Cassat and Skaar, 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cassat and Skaar, 2013 source
Not checked in the free run.
The paper relies on this without support.
The main reservoir of iron in the host is within erythrocytes, where iron is bound to heme in hemoglobin.
“The main reservoir of iron in the host lies within erythrocytes, where iron is sequestered and bound to heme within hemoglobin.”
The paper relies on this without support.
The mouse systemic infection model is informative for human S. aureus pathogenesis despite known species differences in virulence factor compatibility.
“S. aureus is remarkably well adapted to the human host, thus multiple virulence factors of this bacterium are not compatible with non-human species frequently used during in vivo studies.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
During infection, S. aureus utilizes leukocidins HlgAB and LukED to lyse erythrocytes and liberate Hb into the bloodstream.
“During infection, S. aureus utilizes the leukocidins HlgAB and LukED to lyse erythrocytes and liberate Hb into the bloodstream [103].”
From Heme Synthesis and Acquisition in Bacterial Pathogens (2016) · cites this paper as [103]
Cites
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Molecular Basis for the Evolution of Species-Specific Hemoglobin Capture by Staphylococcus aureus
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Host–Receptor Post-Translational Modifications Refine Staphylococcal Leukocidin Cytotoxicity
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Microbiome-Independent Effects of Antibiotics in a Murine Model of Nosocomial Infections
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Self-citationHeme acquisition and tolerance in Gram-positive model bacteria: An orchestrated balance
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Aspartic Acid Residue 51 of SaeR Is Essential for Staphylococcus aureus Virulence
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Immune Evasion byStaphylococcus aureus
de Jong, N. W. M., van Kessel, K. P. M., & van Strijp, J. A. G. (2019) · ASM Press eBooks · doi:10.1128/9781683670131.ch39 · Cited by 11 · see citing works
Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins
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The Small RNA Teg41 Is a Pleiotropic Regulator of Virulence in Staphylococcus aureus
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Self-citation
- Authors
- Spaan, A. N., Reyes-Robles, T., Badiou, C., Cochet, S., Boguslawski, K. M., Yoong, P., Day, C. J., de Haas, C. J. C., van Kessel, K. P. M., Vandenesch, F., Jennings, M. P., Le Van Kim, C., Colin, Y., van Strijp, J. A. G., Henry, T., & Torres, V. J.
- Affiliations
- Lyon 1 Université (FR)
- Inserm (FR)
- New York University (US)
- Griffith University (AU)
- Corresponding author
- Henry, Thomas
- Torres, Victor J.
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 18
- Issue
- 3
- Pages
- 363-370
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC4578157
- OpenAlex
- W1941322164
- Semantic Scholar
- f3cbfc81558b451bf7222a594f9ea92667aa6f6e
- Cited by
- 114
- References
- 47
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 14 · 2023: 14 · 2022: 8 · 2021: 8 · 2020: 12 · 2019: 12 · 2018: 15 · 2017: 7 · 2016: 6 · 2015: 3
- FWCI
- 8.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Griffith Research Online (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-12-BSV3-0003)
- National Institute of General Medical Sciences (T32GM007308)
- National Institute of Allergy and Infectious Diseases (F31AI112290, T32AI007180, R01AI105129, F32AI098395, R01AI099394)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Staphylococcus aureus, DARC, hemolysis, hemolytic toxin, iron acquisition, host-pathogen interaction, receptor binding
- MeSH terms
- Duffy Blood-Group System, Erythrocytes, Hemolysis, Humans, Leukocidins, Protein Binding, Receptors, Cell Surface, Staphylococcus aureus, Host-Pathogen Interactions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
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