Institute of Medical Microbiology, University Hospital of Münster, Germany.
PLoS Pathog. 2010 Jan 8;6(1):e1000715. doi: 10.1371/journal.ppat.1000715.
The role of the pore-forming Staphylococcus aureus toxin Panton-Valentine leukocidin (PVL) in severe necrotizing diseases is debated due to conflicting data from epidemiological studies of community-associated methicillin-resistant S. aureus (CA-MRSA) infections and various murine disease-models. In this study, we used neutrophils isolated from different species to evaluate the cytotoxic effect of PVL in comparison to other staphylococcal cytolytic components. Furthermore, to study the impact of PVL we expressed it heterologously in a non-virulent staphylococcal species and examined pvl-positive and pvl-negative clinical isolates as well as the strain USA300 and its pvl-negative mutant. We demonstrate that PVL induces rapid activation and cell death in human and rabbit neutrophils, but not in murine or simian cells. By contrast, the phenol-soluble modulins (PSMs), a newly identified group of cytolytic staphylococcal components, lack species-specificity. In general, after phagocytosis of bacteria different pvl-positive and pvl-negative staphylococcal strains, expressing a variety of other virulence factors (such as surface proteins), induced cell death in neutrophils, which is most likely associated with the physiological clearing function of these cells. However, the release of PVL by staphylococcal strains caused rapid and premature cell death, which is different from the physiological (and programmed) cell death of neutrophils following phagocytosis and degradation of virulent bacteria. Taken together, our results question the value of infection-models in mice and non-human primates to elucidate the impact of PVL. Our data clearly demonstrate that PVL acts differentially on neutrophils of various species and suggests that PVL has an important cytotoxic role in human neutrophils, which has major implications for the pathogenesis of CA-MRSA infections.
由于社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）感染的流行病学研究和各种小鼠疾病模型的数据相互矛盾，关于形成孔的金黄色葡萄球菌毒素潘顿-瓦伦丁白细胞毒素（PVL）在严重坏死性疾病中的作用存在争议。在这项研究中，我们使用来自不同物种的中性粒细胞来评估 PVL 与其他葡萄球菌细胞溶解成分相比的细胞毒性作用。此外，为了研究 PVL 的影响，我们在一种非毒性葡萄球菌物种中异源表达它，并研究了 pvl 阳性和 pvl 阴性临床分离株以及 USA300 菌株及其 pvl 阴性突变体。我们证明 PVL 可快速诱导人和兔中性粒细胞的激活和细胞死亡，但不会诱导鼠或猿细胞。相比之下，新发现的一组细胞溶解葡萄球菌成分酚可溶性调节素（PSMs）缺乏种特异性。一般来说，吞噬细菌后，不同的 pvl 阳性和 pvl 阴性葡萄球菌菌株，表达各种其他毒力因子（如表面蛋白），会导致中性粒细胞死亡，这很可能与这些细胞的生理清除功能有关。然而，葡萄球菌菌株释放的 PVL 会导致中性粒细胞迅速和过早死亡，这与吞噬和降解毒性细菌后中性粒细胞的生理（和程序性）死亡不同。总的来说，我们的结果对使用小鼠和非人类灵长类动物感染模型来阐明 PVL 的影响提出了质疑。我们的数据清楚地表明，PVL 对不同物种的中性粒细胞作用不同，并表明 PVL 在人中性粒细胞中具有重要的细胞毒性作用，这对 CA-MRSA 感染的发病机制有重大影响。
