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

Tamara Reyes-Robles, Francis Alonzo III, Lina Kozhaya, D. Borden Lacy, Derya Unutmaz, and Victor J. Torres. Cell Host Microbe (2013) 14: 453-459

Speaker: Wei-Ting Li (李瑋庭)                  Time: 13:10~14:00, Oct. 22, 2014

Commentator: Dr. Shu-Ying Wang (王淑鶯 老師)  Place: Room 601

Abstract:

Staphylococcus aureus is a Gram-positive coccal bacterium responsible for many diseases, from skin and soft-tissue infections to more invasive diseases including pneumonia and sepsis¹. S. aureus disease-associated strains often produce leukotoxins, a pore-forming toxin that targets and kills human immune cells to evade host immune response. Recently, the authors found that an S. aureus-secreted leukotoxin, LukED, could target the chemokine receptor CCR5 to kill human memory T cells, macrophages and dendritic cells². The authors have previously found that this toxin also kills human neutrophils (polymorphonuclear cells; PMNs), which lack CCR5, and the CCR5^-/- patient’s peripheral blood monocytes, suggesting that there may be alternative cellular receptors on these cells. In this study, they discovered that the human embryonic kidney cell line expressing the chemokine receptors CXCR1 or CXCR2 by transfection were susceptible to LukED. In addition, the majority of primary human PMNs and monocytes expressed both CXCR1 and CXCR2 on cell surface and they were susceptibility to LukED. These suggest that LukED might kill leukocytes via CXCR1 and CXCR2. Indeed, binding experiment and pull-down assay revealed that the LukE subunit specifically bound to CXCR1 and CXCR2 on PMNs, and this interaction was inhibited by CXCL8, the high-affinity endogenous ligand of CXCR1 and CXCR2. By comparing the amino acid sequences of two homologous S. aureus-secreted leukotoxins, LukE and LukS-PV, the authors identified five significant sequence divergence regions, DR1-DR5, which were hypothesized to play a role in receptor recognition³. Amino acid change in DR4 (LukE^DR4) impaired cytotoxicity of LukE^DR4D toxin toward PMNs due to loss of CXCR1 and CXCR2-binding ability. The authors also demonstrated in the mouse that the LukED-mediated killing of CXCR1- and CXCR2-positive cells contributed to S. aureus pathogenesis and decreased survival of the host. Thus, LukED is a versatile toxin that eliminates many leukocytes involved in innate and adaptive immune to suppress the host immune response to S. aureus.

References:

1.     DeLeo, F.R., and Chambers, H.F. (2009). Reemergence of antibiotic-resistant Staphylococcus aureus in the genomics era. J. Clin. Invest. 119, 2464–2474.

2.     Alonzo, F., 3rd, Kozhaya, L., Rawlings, S.A., Reyes-Robles, T., DuMont, A.L., Myszka, D.G., Landau, N.R., Unutmaz, D., and Torres, V.J. (2013). CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature 493, 51–55.

3.     Guillet, V., Roblin, P., Werner, S., Coraiola, M., Menestrina, G., Monteil, H.,Pre´ vost, G., and Mourey, L. (2004). Crystal structure of leucotoxin S component: new insight into the staphylococcal beta-barrel pore-forming toxins. J. Biol. Chem. 279, 41028–41037.