The staphylococcal toxins γ-haemolysin AB and CB differentially target phagocytes by employing specific chemokine receptors

Abstract

Evasion of the host phagocyte response by Staphylococcus aureus is crucial to successful infection with the pathogen. γ-Hemolysin AB and CB (HlgAB, HlgCB) are bicomponent pore-forming toxins present in almost all human S. aureus isolates. Cellular tropism and contribution of the toxins to S. aureus pathophysiology are poorly understood. Here, we identify the chemokine receptors CXCR1, CXCR2 and CCR2 as targets for HlgAB, and the complement receptors C5aR and C5L2 as targets for HlgCB. The receptor expression patterns allow the toxins to efficiently and differentially target phagocytic cells. Murine neutrophils are resistant to HlgAB and HlgCB. CCR2 is the sole murine receptor orthologue compatible with γ-Hemolysin. In a murine peritonitis model, HlgAB contributes to S. aureus bacteremia in a CCR2-dependent manner. HlgAB-mediated targeting of CCR2+ cells highlights the involvement of inflammatory macrophages during S. aureus infection. Functional quantification identifies HlgAB and HlgCB as major secreted staphylococcal leukocidins.

Humanized Mice Exhibit Increased Susceptibility toStaphylococcus aureusPneumonia

“…Also, direct comparison of the immune response between these mice and humans is not possible because of the production of cytokines from both stromal and immune cells in humans. The humanized mice used in these studies, while having excellent reconstitution of T cells, monocytes, and macrophages, all of which are targets of S. aureus toxins [4,14,15,19,21], does not yet fully replicate a functioning human immune system. It has been recognized that neutrophil numbers are not optimal in the peripheral blood of humanized mice, and hence there may be a more limited number of cells to recruit; thus, this is an area to improve in subsequent models [38,39].…”

“…The improved clearance of the Δpvl mutant was evident in the substantially less lung consolidation and loss of alveolar airspaces than was associated with infection due to the WT USA300 or the complemented mutant ( Figure 4E and 4F ). Since there are additional S. aureus toxins that target the human C5a receptors [4], the contribution of PVL itself was confirmed by treating mice with a tetravalent bispecific PVL antibody, which was previously demonstrated to confer protection in a rabbit model of pneumonia [29], compared with mice treated with vehicle control. Mice treated with PVL antibody but not an IgG control had 76% fewer bacteria in the lung (1.9 × 10 8 vs 0.45 × 10 8 CFU/mL; P < .05) with a similar trend in the airway (5.3 × 10 5 vs 2.3 × 10 5 CFU/mL; Figure 4G and 4H).…”

“…Nasal colonization with S. aureus is associated with subsequent infection and occurs in up to 30% of unselected individuals [1,2]. Yet, despite the prevalence of S. aureus in the general population, the specific correlates of protective immunity against staphylococcal infection are not well defined.A number of S. aureus virulence factors, including several bicomponent toxins, are specific for human receptors [3,4]. One of the first of these human-specific toxins to be fully characterized was Panton-Valentine leukocidin (PVL), which targets neutrophils, macrophages, and monocytes [5,6].…”

“…The molecular basis for this discrepancy was ascribed to the high human (and rabbit) specificity for the PVL receptors, C5aR and C5L2 [14]. Additional toxins, LukAB and HlgCB, have also been shown to have high specificity to the human forms of the receptors, CD11b and C5aR, respectively [4,14,15]. These toxins with human receptor specificity are in contrast to those such as α-toxin, which recognizes ADAM-10 on murine cells, as well as human cells [16].…”

“…A number of S. aureus virulence factors, including several bicomponent toxins, are specific for human receptors [3,4]. One of the first of these human-specific toxins to be fully characterized was Panton-Valentine leukocidin (PVL), which targets neutrophils, macrophages, and monocytes [5,6].…”