title: 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.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Alonzo
authors.forename: Lina
authors.initials: L
authors.lastname: Kozhaya
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Rawlings
authors.forename: Tamara
authors.initials: T
authors.lastname: Reyes-Robles
authors.forename: Ashley L
authors.initials: AL
authors.lastname: DuMont
authors.forename: David G
authors.initials: DG
authors.lastname: Myszka
authors.forename: Nathaniel R
authors.initials: NR
authors.lastname: Landau
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Torres
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism*; D065100:CCR5 Receptor Antagonists; D016923:Cell Death; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005098:Exotoxins / Q000378:metabolism*; D005260:Female; D006801:Humans; D057131:Immune Evasion; D007156:Immunologic Memory; D019169:Jurkat Cells; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000276:immunology / Q000472:pathogenicity*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D065100:CCR5 Receptor Antagonists; D005098:Exotoxins; D019713:Receptors, CCR5; C018579:leukotoxin