CCR5 is a receptor for Staphylococcus aureus leukotoxin ED
By F. Iii, L. Kozhaya, Stephen A. Rawlings, Tamara Reyes-Robles, Ashley L. DuMont, D. Myszka, N. Landau, D. Unutmaz, Victor J. Torres. 2012
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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.
Subfields: Immunology, Microbiology, Virology
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Citations in the corpus
- Staphylococcus aureus toxins (2013, background): “Initially often believed to function in a receptor-independent fashion, the discovery of the LukDE receptor (CCR5) [12 ], and the subsequent discoveries of the PVL and LukGH (LukAB) receptors (C5aR, C5L2 and CD11b, respectively) [13,14 ], clearly showed that these toxins require receptor interaction”
- Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5 (2016, methodology): “CCR5 is one of four receptors targeted by LukED (5, 24, 25).”
- The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus (2014, methodology): “LukED and PVL both recognize GPCRs that are important for immune cell activation and chemotaxis (199, 227, 230).”
- Pathogenicity and virulence of Staphylococcus aureus (2021, background): “The S subunit recognizes a membrane protein receptor [a chemokine receptor for PVL and LukED [150,151] and an integrin for LukAB/GH [152]] and then recruits the F subunit, leading first to dimerization and ultimately, after considerable structural changes that facilitate membrane insertion, to the f”