Counter inhibition between leukotoxins attenuates Staphylococcus aureus virulence.

Pauline Yoong,Victor J Torres

doi:10.1038/ncomms9125

Abstract

Staphylococcus aureus subverts host defences by producing a collection of virulence factors including bi-component pore-forming leukotoxins. Despite extensive sequence conservation, each leukotoxin has unique properties, including disparate cellular receptors and species specificities. How these toxins collectively influence S. aureus pathogenesis is unknown. Here we demonstrate that the leukotoxins LukSF-PV and LukED antagonize each other's cytolytic activities on leukocytes and erythrocytes by forming inactive hybrid complexes. Remarkably, LukSF-PV inhibition of LukED haemolytic activity on both human and murine erythrocytes prevents the release of nutrients required for in vitro bacterial growth. Using in vivo murine models of infection, we show that LukSF-PV negatively influences S. aureus virulence and colonization by inhibiting LukED. Thus, while S. aureus leukotoxins can certainly injure immune cells, the discovery of leukotoxin antagonism suggests that they may also play a role in reducing S. aureus virulence and maintaining infection without killing the host.

Highlights

Staphylococcus aureus subverts host defences by producing a collection of virulence factors including bi-component pore-forming leukotoxins
We demonstrate the lytic activities of hybrid LukSF-PV and leukotoxin ED (LukED) leukotoxins by employing the versatile human promyelocytic HL60 cell line, which can be differentiated into neutrophil-like cells and macrophage-like cells using dimethylsulfoxide and phorbol 12-myristate 13-acetate, respectively[26] (Table 1 and Supplementary Fig. 2A,B)
Leukotoxins have increasingly been recognized as important S. aureus virulence factors since their discovery more than a century ago[6]

Summary

Introduction

Staphylococcus aureus subverts host defences by producing a collection of virulence factors including bi-component pore-forming leukotoxins. Among the virulence factors encoded by S. aureus are a family of five leukotoxins, which include the Panton–Valentine leukocidin (LukSF-PV), leukotoxin ED (LukED), gamma hemolysin (which exists as two toxins: HlgAB and HlgCB) and leukotoxin AB (LukAB, known as LukGH)[6] These toxins target an extensive range of the body’s immune cells for destruction, which is thought to play a crucial role in immune evasion by S. aureus by promoting bacterial survival and proliferation[6,7]. These leukotoxins are classified as ‘bi-component’ as each is made up of two protein subunits grouped into ‘S’ (for example, LukS-PV, LukE, HlgA, HlgC and LukA) and ‘F’ (for example, LukF-PV, LukD, HlgB and LukB) families, with amino acid sequence conservation within each family ranging from B30 to 480% How leukotoxins contribute as a group to S. aureus pathogenesis in vivo is poorly understood

Methods

Results

Conclusion