title: Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection.
abstract: 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.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Reyes-Robles
authors.forename: Francis
authors.initials: F
authors.lastname: Alonzo
authors.forename: Lina
authors.initials: L
authors.lastname: Kozhaya
authors.forename: D Borden
authors.initials: DB
authors.lastname: Lacy
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Torres
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005098:Exotoxins / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects*; D023062:Receptors, Interleukin-8A / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000473:pathology; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000472:pathogenicity*; D016019:Survival Analysis; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D005098:Exotoxins; C115218:LukD protein, Staphylococcus aureus; C115217:LukE protein, Staphylococcus aureus; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B