The staphylococcal toxins γ-haemolysin AB and CB differentially target phagocytes by employing specific chemokine receptors (original) (raw)
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Cell Host & Microbe, 2013
The Staphylococcus aureus leukotoxin ED (LukED) is a pore-forming toxin required for the lethality associated with bacteremia in murine models. LukED targets the chemokine receptor CCR5 to kill T lymphocytes, macrophages, and dendritic cells. LukED also kills CCR5-deficient cells, like neutrophils, suggesting the existence of additional cellular receptors. Here, we identify the chemokine receptors CXCR1 and CXCR2 as the targets of LukED on neutrophils. The LukE subunit binds neutrophils in a specific and saturable manner, and this interaction is inhibited by CXCL8, the high-affinity endogenous ligand of CXCR1 and CXCR2. LukED recognition of CXCR1 and CXCR2 promotes the killing of monocytes and neutrophils in vitro. LukED-mediated targeting of CXCR1 and CXCR2 + cells contributes to S. aureus pathogenesis and facilitates lethality in systemically infected mice. Thus, LukED is a versatile toxin that endows S. aureus with the ability to simultaneously disarm both innate and adaptive compartments of the host immune response. Cell Host & Microbe LukED Kills Neutrophils via CXCR1 and CXCR2
The Journal of Infectious Diseases, 2008
Background. Staphylococcus aureus ␣-toxin is a major virulence factor, but its mechanism of action in vivo is incompletely understood. Methods. We examined the role of ␣-toxin in S. aureus pneumonia using the mouse model of intranasal lung infection with S. aureus strain 8325-4 (hla ϩ S. aureus) and an ␣-toxindeficient mutant strain made on the 8325-4 background (hla Ϫ S. aureus). Results. Intranasal infection of mice with hla Ϫ S. aureus resulted in substantially less lung injury and inflammation, pulmonary edema, and tissue bacterial burden than did infection with hla ϩ S. aureus. Furthermore, fewer mice infected with hla Ϫ S. aureus died of the infection, compared with those infected with hla ϩ S. aureus. Levels of the CXC chemokines keratinocyte-derived chemokine and macrophage inflammatory protein-2 were significantly lower in the airways of mice infected with hla Ϫ S. aureus, and this difference was the result of reduced secretion of newly synthesized chemokines into the airway. Consistent with these data, significantly fewer neutrophils were present in the airways and lungs of mice infected with hla Ϫ S. aureus, compared with those infected with hla ϩ S. aureus. Conclusions. These data suggest that ␣-toxin enhances virulence by facilitating the generation of CXC chemokine gradients and stimulating chemokine-induced neutrophil influx in S. aureus pneumonia. Staphylococcus aureus is a major gram-positive bacterial pathogen that can cause a wide variety of infections and toxinoses, such as cellulitis, fasciitis, food poisoning, toxic shock syndrome, sepsis, endocarditis, osteomyelitis, and pneumonia [1]. Historically, S. aureus has been a leading cause of nosocomial infections, but it is also rapidly becoming an important community-acquired pathogen [2, 3]. Invasive S. aureus infections, particularly those caused by methicillin-resistant S. aureus (MRSA) strains, are a significant cause of mortality and morbidity [4]. Along with bacteremia, S. aureus pneu
CCR5 is a receptor for Staphylococcus aureus leukotoxin ED
2012
Pore-forming toxins are critical virulence factors for many bacterial pathogens and are central to Staphylococcus aureus-mediated killing of host cells. S. aureus encodes pore-forming bi-component leukotoxins that are toxic towards neutrophils, but also specifically target other immune cells. Despite decades since the first description of staphylococcal leukocidal activity, the host factors responsible for the selectivity of leukotoxins towards different immune cells remain unknown.
Journal of immunology (Baltimore, Md. : 1950), 2015
Staphylococcus aureus is well adapted to the human host. Evasion of the host phagocyte response is critical for successful infection. The staphylococcal bicomponent pore-forming toxins Panton-Valentine leukocidin LukSF-PV (PVL) and γ-hemolysin CB (HlgCB) target human phagocytes through interaction with the complement receptors C5aR1 and C5aR2. Currently, the apparent redundancy of both toxins cannot be adequately addressed in experimental models of infection because mice are resistant to PVL and HlgCB. The molecular basis for species specificity of the two toxins in animal models is not completely understood. We show that PVL and HlgCB feature distinct activity toward neutrophils of different mammalian species, where activity of PVL is found to be restricted to fewer species than that of HlgCB. Overexpression of various mammalian C5a receptors in HEK cells confirms that cytotoxicity toward neutrophils is driven by species-specific interactions of the toxins with C5aR1. By taking adv...
Staphylococcus aureus Staphopain A inhibits CXCR2-dependent neutrophil activation and chemotaxis
The EMBO Journal, 2012
The CXC chemokine receptor 2 (CXCR2) on neutrophils, which recognizes chemokines produced at the site of infection, plays an important role in antimicrobial host defenses such as neutrophil activation and chemotaxis. Staphylococcus aureus is a successful human pathogen secreting a number of proteolytic enzymes, but their influence on the host immune system is not well understood. Here, we identify the cysteine protease Staphopain A as a chemokine receptor blocker. Neutrophils treated with Staphopain A are unresponsive to activation by all unique CXCR2 chemokines due to cleavage of the N-terminal domain, which can be neutralized by specific protease inhibitors. Moreover, Staphopain A inhibits neutrophil migration towards CXCR2 chemokines. By comparing a methicillin-resistant S. aureus (MRSA) strain with an isogenic Staphopain A mutant, we demonstrate that Staphopain A is the only secreted protease with activity towards CXCR2. Although the inability to cleave murine CXCR2 limits in-vivo studies, our data indicate that Staphopain A is an important immunomodulatory protein that blocks neutrophil recruitment by specific cleavage of the N-terminal domain of human CXCR2.
2012
One key aspect of the virulence of Staphylococcus aureus lies in its ability to target the host cell membrane with a large number of membrane-damaging toxins and peptides. In this review, we describe the hemolysins, the bi-component leukocidins (which include the Panton Valentine leukocidin, LukAB/GH, and LukED), and the cytolytic peptides (phenol soluble modulins). While at first glance, all of these factors might appear redundant, it is now clear that some of these factors play specific roles in certain S. aureus life stages and diseases or target specific cell types or species. In this review, we present an update of the literature on toxin receptors and their cell type and species specificities. Furthermore, we review epidemiological studies and animal models illustrating the role of these membranedamaging factors in various diseases. Finally, we emphasize the interplay of these factors with the host immune system and highlight all their non-lytic functions.
PLoS Pathogens, 2013
The success of Staphylococcus aureus as a human pathogen is influenced by its ability to elaborate factors that prevent infection resolution by the host immune system. Such immune-altering factors include complement inhibitory molecules, antibody binding proteins, super-antigens, as well as potent cytolytic peptides and pore-forming toxins. Here, we discuss one class of immune cell-targeting toxins, the bi-component leukotoxins. These toxins are believed to form octameric oligomers of alternating subunits on the surface of host cells and insert bbarrel pores into cell membranes leading to osmotic imbalance and cell lysis [1]. We will discuss the reemerging interest in leukotoxins as potent virulence factors with defined cellular targets, the implications of their lethal and sublethal cellular effects, as well as challenges that have restricted understanding of their functional activity in vivo, while emphasizing areas of interest for future exploration. In addition, we highlight studies supporting the development of antileukotoxin antibodies and immunization strategies as potential modalities to counter S. aureus infection.
Counter inhibition between leukotoxins attenuates Staphylococcus aureus virulence
Nature Communications, 2015
Staphylococcus aureus subverts host defences by producing a collection of virulence factors including bi-component pore-forming leukotoxins. Despite extensive sequence conservation, each leukotoxin has unique properties, including disparate cellular receptors and species specificities. How these toxins collectively influence S. aureus pathogenesis is unknown. Here we demonstrate that the leukotoxins LukSF-PV and LukED antagonize each other’s cytolytic activities on leukocytes and erythrocytes by forming inactive hybrid complexes. Remarkably, LukSF-PV inhibition of LukED haemolytic activity on both human and murine erythrocytes prevents the release of nutrients required for in vitro bacterial growth. Using in vivo murine models of infection, we show that LukSF-PV negatively influences S. aureus virulence and colonization by inhibiting LukED. Thus, while S. aureus leukotoxins can certainly injure immune cells, the discovery of leukotoxin antagonism suggests that they may also play a r...
Toxins, 2018
Cytolytic pore-forming toxins including alpha hemolysin (Hla) and bicomponent leukotoxins play an important role in the pathogenesis of Staphylococcus aureus. These toxins kill the polymorphonuclear phagocytes (PMNs), disrupt epithelial and endothelial barriers, and lyse erythrocytes to provide iron for bacterial growth. The expression of these toxins is regulated by the two-component sensing systems Sae and Agr. Here, we report that a point mutation (L18P) in SaeS, the histidine kinase sensor of the Sae system, renders the S. aureus Newman hemolytic activity fully independent of Hla and drastically increases the PMN lytic activity. Furthermore, this Hla-independent activity, unlike Hla itself, can lyse human erythrocytes. The Hla-independent activity towards human erythrocytes was also evident in USA300, however, under strict agr control. Gene knockout studies revealed that this Hla-independent Sae-regulated activity was entirely dependent on gamma hemolysin A subunit (HlgA). In co...
Molecular …, 2007
The chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is reported to bind to the receptors for C5a and formylated peptides and has been proposed as a promising lead for the development of new anti-inflammatory compounds. Here we have examined the receptor specificity and mode of action of recombinant CHIPS28–149 and also the immune response to CHIPS28–149 in patients with S. aureus infections and in uninfected controls. Recombinant CHIPS28–149 bound with high affinity to the human C5a receptor (C5aR), but had low affinity for the second C5a receptor, C5L2, and the formyl peptide receptor, FPR. Although ligand binding to C5aR was potently inhibited, CHIPS28–149 had much weaker effects on ligand binding to C5L2 and FPR. Similarly, CHIPS28–149 potently inhibited the ligand-induced activation of C5aR but was less potent at inhibition via FPR. NMR studies showed that CHIPS28–149 bound directly to the N-terminus of C5aR but not C5L2, and CHIPS28–149 residues involved in the interaction were identified by chemical shift analysis. All human sera examined contained high titres of IgG and IgA reactivity against CHIPS28–149, and no correlation was observed between infection status at the time of serum collection and antibody titre. Individual serum samples promoted or inhibited the binding of CHIPS28–149 to C5aR, or had no effect. IgG depletion of serum samples abrogated the effects on CHIPS binding, demonstrating that these were antibody mediated. Sera from infected individuals were more likely to inhibit CHIPS28–149 binding than sera from healthy controls. However, high antibody titres correlated well with both inhibition and enhancement of CHIPS28–149 binding to C5aR; this suggests that the inhibitory effect relates to epitope specificity rather than greater antibody binding. We conclude that CHIPS is likely to be too immunogenic to be used as an anti-inflammatory treatment but that some antibodies against CHIPS may be useful in the treatment of S. aureus infections.