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CCR5 is a receptor for Staphylococcus aureus leukotoxin ED.

ABSTRACT: 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. Here we identify the human immunodeficiency virus (HIV) co-receptor CCR5 as a cellular determinant required for cytotoxic targeting of subsets of myeloid cells and T lymphocytes by the S. aureus leukotoxin ED (LukED). We further demonstrate that LukED-dependent cell killing is blocked by CCR5 receptor antagonists, including the HIV drug maraviroc. Remarkably, CCR5-deficient mice are largely resistant to lethal S. aureus infection, highlighting the importance of CCR5 targeting in S. aureus pathogenesis. Thus, depletion of CCR5(+) leukocytes by LukED suggests a new immune evasion mechanism of S. aureus that can be therapeutically targeted.

SUBMITTER: Alonzo F

PROVIDER: S-EPMC3536884 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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CCR5 is a receptor for Staphylococcus aureus leukotoxin ED.

Alonzo Francis F Kozhaya Lina L Rawlings Stephen A SA Reyes-Robles Tamara T DuMont Ashley L AL Myszka David G DG Landau Nathaniel R NR Unutmaz Derya D Torres Victor J VJ

Nature 20121212 7430

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. Here we iden ...[more]

PMID: 23235831

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Project description:Leukocidin ED (LukED) is a bicomponent pore-forming toxin produced by Staphylococcus aureus that lyses host cells by targeting the chemokine receptors CC chemokine receptor type 5 (CCR5), CXCR1, CXCR2, and DARC. In addition to its role as a receptor for LukED, CCR5 is the major coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and has been extensively studied. To compare how LukED and HIV-1 target CCR5, we analyzed their respective abilities to use CCR5/CCR2b chimeras to mediate cytotoxicity and virus entry. These analyses showed that the second and third extracellular loops (ECL) of CCR5 are necessary and sufficient for LukED to target the receptor and promote cell lysis. In contrast, the second ECL of CCR5 is necessary but not sufficient for HIV-1 infectivity. The analysis of CCR5 point mutations showed that glycine-163 is critical for HIV-1 infectivity, while arginine-274 and aspartic acid-276 are critical for LukED cytotoxicity. Point mutations in ECL2 diminished both HIV-1 infectivity and LukED cytotoxicity. Treatment of cells with LukED did not interfere with CCR5-tropic HIV-1 infectivity, demonstrating that LukED and the viral envelope glycoprotein use nonoverlapping sites on CCR5. Analysis of point mutations in LukE showed that amino acids 64 to 69 in the rim domain are required for CCR5 targeting and cytotoxicity. Taking the results together, this study identified the molecular basis by which LukED targets CCR5, highlighting the divergent molecular interactions evolved by HIV-1 and LukED to interact with CCR5. The bicomponent pore-forming toxins are thought to play a vital role in the success of Staphylococcus aureus as a mammalian pathogen. One of the leukocidins, LukED, is necessary and sufficient for lethality in mice. At the molecular level, LukED causes cell lysis through binding to specific cellular receptors. CCR5 is one of the receptors targeted by LukED and is the major coreceptor for CCR5-tropic HIV-1. While the molecular interaction of CCR5 and HIV-1 is well characterized, the means by which LukED interacts with CCR5 is less clear. In this study, we demonstrated that receptor specificity is conferred through unique interactions between key domains on CCR5 and LukE. Although HIV-1 and LukED target the same receptor, our data demonstrated that they interact with CCR5 differently, highlighting the molecular complexity of host-pathogen interactions.

Project description:BackgroundThe bicomponent leukotoxins and the pyrogenic toxin superantigens (PTSAgs) are important virulence factors of Staphylococcus aureus. It is necessary to survey the prevalence and expression of these toxin-encoding genes for understanding the possible pathogenic capacity of S. aureus to cause disease.MethodsFive leukotoxin genes and thirteen PTSAg determinants were detected for 177 S. aureus isolates from blood (n = 88) and wound (n = 89) infections by Polymerase Chain Reaction (PCR). The expression of leukotoxin ED (lukED) was determined by quantitative real-time PCR (qRT-PCR). The genetic backgrounds of isolates were analyzed by Staphylococcal Cassette Chromosome mec (SCCmec) typing (for methicillin-resistant S. aureus isolates), Pulsed-Field Gel Electrophoresis (PFGE), accessory gene regulator (agr) typing and Multilocus Sequence Typing (MLST, for representative isolates based on PFGE type) methods.Results99.4% (176/177) isolates contained at least one of leukotoxin genes. Among them, 94.9% (168/177), 81.4% (144/177) and 67.8% (120/177) isolates harbored hlgBC, lukED and lukAB, respectively. Compared to leukotoxin genes, there was a relatively lower overall prevalence of PTSAg genes [99.4% versus 72.9% (129/177), P < 0.001], and they were organized in 59 patterns, with the most common combination of the egc cluster with or without other PTSAg genes. Genetic analysis showed the distributions of certain toxin genes were associated with the genetic backgrounds of isolates. The egc cluster was a common feature of CC5 isolates, among which ST5 and ST764 isolates harbored more PTSAg genes. The lukED was not present in ST398 isolates, and its expression was quite different among isolates. No significant correlations were observed between the lukED expression levels of strains and the ST or agr types.ConclusionsThe present study elucidated the distribution of leukotoxin and PTSAg genes and the expression of lukED in blood and wound isolates, and analyzed the relationship between them with genetic characteristics of isolates. These data improve the current understanding of the possible pathogenicity of S. aureus.

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CCR5 is a receptor for Staphylococcus aureus leukotoxin ED.

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CCR5 is a receptor for Staphylococcus aureus leukotoxin ED.

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