Staphylococcus aureus Leukotoxin ED Targets the Chemokine Receptors CXCR1 and CXCR2 to Kill Leukocytes and Promote Infection

• Published in: Cell host & microbe Vol. 14; no. 4; pp. 453 - 459
• Main Authors: Reyes-Robles, Tamara, Alonzo, Francis, Kozhaya, Lina, Lacy, D. Borden, Unutmaz, Derya, Torres, Victor J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.10.2013
• Subjects: Animals; Bacterial Proteins - metabolism; Cell Survival - drug effects; Disease Models, Animal; Exotoxins - metabolism; Host-Pathogen Interactions; Humans; Mice; Monocytes - drug effects; Neutrophils - drug effects; Receptors, Interleukin-8A - metabolism; Receptors, Interleukin-8B - metabolism; Staphylococcal Infections - pathology; Staphylococcus aureus - metabolism; Staphylococcus aureus - pathogenicity; Survival Analysis; Virulence
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2013.09.005

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. [Display omitted] •S. aureus LukED targets CXCR1 and CXCR2 to kill monocytes and PMNs•LukE-CXCR1 and LukE-CXCR2 binding on PMNs is blocked by CXCL8•LukE divergence region 4 is required for LukED targeting of CXCR1 and CXCR2+ cells•LukED targeting of CXCR1 and CXCR2 contributes to S. aureus pathogenesis