IsdB-dependent Hemoglobin Binding Is Required for Acquisition of Heme by Staphylococcus aureus

Pishchany, Gleb; Sheldon, Jessica R.; Dickson, Claire F.; Alam, Tauqeer; Read, Timothy D.; Gell, David A.; Heinrichs, David E.; Skaar, Eric P.

doi:10.1093/infdis/jit817

Cited by 74 publications

(106 citation statements)

References 48 publications

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“…We observed that HlgAB and LukED were each capable of promoting S. aureus growth (Figure 4C). To determine if this growth was dependent of hemoglobin acquisition, we used an isogenic strain lacking the S. aureus hemoglobin receptors IsdB and IsdH (Δ isdBH ) (Pishchany et al, 2014; Torres et al, 2006). In contrast to wild type (WT) S. aureus , the Δ isdBH strain was significantly growth impaired in medium supplemented with cell-free extracts from toxin treated erythrocytes (Figure 4C).…”

Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus Targets the Duffy Antigen Receptor for Chemokines (DARC) to Lyse Erythrocytes

Spaan¹,

Reyes‐Robles²,

Badiou³

et al. 2015

Cell Host & Microbe

137

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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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Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus Targets the Duffy Antigen Receptor for Chemokines (DARC) to Lyse Erythrocytes

Spaan¹,

Reyes‐Robles²,

Badiou³

et al. 2015

Cell Host & Microbe

137

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“…Should heme no longer be accessible as an iron source, we hypothesize that "active" SbnI would allow transcription of downstream sbn genes and that pre-formed L-Dap in the cell would allow for a rapid transition to SB-mediated iron uptake. The fine-tuning of SB and heme uptake systems in S. aureus is of interest because both sbn and isd genes have been implicated in virulence in S. aureus models of infection (16,25,26,(43)(44)(45)(46). …”

Section: Discussionmentioning

confidence: 99%

A Heme-responsive Regulator Controls Synthesis of Staphyloferrin B in Staphylococcus aureus

Laakso¹,

Marolda²,

Pinter

et al. 2016

Journal of Biological Chemistry

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Staphylococcus aureus possesses a multitude of mechanisms by which it can obtain iron during growth under iron starvation conditions. It expresses an effective heme acquisition system (the iron-regulated surface determinant system), it produces two carboxylate-type siderophores staphyloferrin A and staphyloferrin B (SB), and it expresses transporters for many other siderophores that it does not synthesize. The ferric uptake regulator protein regulates expression of genes encoding all of these systems. Mechanisms of fine-tuning expression of ironregulated genes, beyond simple iron regulation via ferric uptake regulator, have not been uncovered in this organism. Here, we identify the ninth gene of the sbn operon, sbnI, as encoding a ParB/Spo0J-like protein that is required for expression of genes in the sbn operon from sbnD onward. Expression of sbnD-I is drastically decreased in an sbnI mutant, and the mutant does not synthesize detectable SB during early phases of growth. Thus, SB-mediated iron acquisition is impaired in an sbnI mutant strain. We show that the protein forms dimers and tetramers in solution and binds to DNA within the sbnC coding region. Moreover, we show that SbnI binds heme and that heme-bound SbnI does not bind DNA. Finally, we show that providing exogenous heme to S. aureus growing in an iron-free medium results in delayed synthesis of SB. This is the first study in S. aureus that identifies a DNA-binding regulatory protein that senses heme to control gene expression for siderophore synthesis.

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“…S. aureus binds free hemoglobin (at nanomolar concentrations in the blood) via the surface-exposed iron-regulated surface determinant (Isd) system. Heme is extracted, brought inside the cell, and degraded within the cytoplasm to access the iron (56). IsdB in particular is one member of the Isd family that binds hemoglobin.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Effects of Cigarette Smoke on Staphylococcal Virulence Phenotypes

et al. 2015

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f Cigarette smoking is the leading preventable cause of death, disease, and disability worldwide. It is well established that cigarette smoke provokes inflammatory activation and impairs antimicrobial functions of human immune cells. Here we explore whether cigarette smoke likewise affects the virulence properties of an important human pathogen, Staphylococcus aureus, and in particular methicillin-resistant S. aureus (MRSA), one of the leading causes of invasive bacterial infections. MRSA colonizes the nasopharynx and is thus exposed to inhalants, including cigarette smoke. MRSA exposed to cigarette smoke extract (CSE-MRSA) was more resistant to macrophage killing (4-fold higher survival; P < 0.0001). CSE-MRSA demonstrated reduced susceptibility to cell lysis (1.78-fold; P ‫؍‬ 0.032) and antimicrobial peptide (AMP) (LL-37) killing (MIC, 8 M versus 4 M). CSE modified the surface charge of MRSA in a dose-dependent fashion, impairing the binding of particles with charge similar to that of AMPs by 90% (P < 0.0001). These changes persisted for 24 h postexposure, suggesting heritable modifications. CSE exposure increased hydrophobicity by 55% (P < 0.0001), which complemented findings of increased MRSA adherence and invasion of epithelial cells. CSE induced upregulation of mprF, consistent with increased MRSA AMP resistance. S. aureus without mprF had no change in surface charge upon exposure to CSE. In vivo, CSE-MRSA pneumonia induced higher mouse mortality (40% versus 10%) and increased bacterial burden at 8 and 20 h postinfection compared to control MRSA-infected mice (P < 0.01). We conclude that cigarette smoke-induced immune resistance phenotypes in MRSA may be an additional factor contributing to susceptibility to infectious disease in cigarette smokers.

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IsdB-dependent Hemoglobin Binding Is Required for Acquisition of Heme by Staphylococcus aureus

Cited by 74 publications

References 48 publications

Staphylococcus aureus Targets the Duffy Antigen Receptor for Chemokines (DARC) to Lyse Erythrocytes

Staphylococcus aureus Targets the Duffy Antigen Receptor for Chemokines (DARC) to Lyse Erythrocytes

A Heme-responsive Regulator Controls Synthesis of Staphyloferrin B in Staphylococcus aureus

Analysis of the Effects of Cigarette Smoke on Staphylococcal Virulence Phenotypes

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