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.
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We thank members of the Torres laboratory, D. R. Littman, M. Lu, and A. Darwin for reading this manuscript. We also thank V. KewalRamani for providing reagents, and S. Polsky for assistance with purification of PBMCs. This research was supported by New York University School of Medicine Development Funds, an American Heart Association Scientist Development Grant (09SDG2060036) to V.J.T. and National Institutes of Health (NIH) grants R56-AI091856-01A1 to V.J.T., NIH training grant T32-AI007180 to F.A., A.L.D. and S.A.R., NIH R42-MH084372-02A1 to D.G.M., and NIH R21-AI087973 and R01-AI065303 grants to D.U.
The authors declare no competing financial interests.
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Alonzo III, F., Kozhaya, L., Rawlings, S. et al. CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature 493, 51–55 (2013). https://doi.org/10.1038/nature11724
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