Tseng Ching Wen, Kyme Pierre, Low Jennifer, Rocha Miguel A, Alsabeh Randa, Miller Loren G, Otto Michael, Arditi Moshe, Diep Binh An, Nizet Victor, Doherty Terence M, Beenhouwer David O, Liu George Y
Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
PLoS One. 2009 Jul 27;4(7):e6387. doi: 10.1371/journal.pone.0006387.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) threatens public health worldwide, and epidemiologic data suggest that the Panton-Valentine Leukocidin (PVL) expressed by most CA-MRSA strains could contribute to severe human infections, particularly in young and immunocompetent hosts. PVL is proposed to induce cytolysis or apoptosis of phagocytes. However, recent comparisons of isogenic CA-MRSA strains with or without PVL have revealed no differences in human PMN cytolytic activity. Furthermore, many of the mouse studies performed to date have failed to demonstrate a virulence role for PVL, thereby provoking the question: does PVL have a mechanistic role in human infection? In this report, we evaluated the contribution of PVL to severe skin and soft tissue infection. We generated PVL mutants in CA-MRSA strains isolated from patients with necrotizing fasciitis and used these tools to evaluate the pathogenic role of PVL in vivo. In a model of necrotizing soft tissue infection, we found PVL caused significant damage of muscle but not the skin. Muscle injury was linked to induction of pro-inflammatory chemokines KC, MIP-2, and RANTES, and recruitment of neutrophils. Tissue damage was most prominent in young mice and in those strains of mice that more effectively cleared S. aureus, and was not significant in older mice and mouse strains that had a more limited immune response to the pathogen. PVL mediated injury could be blocked by pretreatment with anti-PVL antibodies. Our data provide new insights into CA-MRSA pathogenesis, epidemiology and therapeutics. PVL could contribute to the increased incidence of myositis in CA-MRSA infection, and the toxin could mediate tissue injury by mechanisms other than direct killing of phagocytes.
社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）威胁着全球公共卫生，流行病学数据表明，大多数CA-MRSA菌株表达的杀白细胞素（PVL）可能导致严重的人类感染，尤其是在年轻且免疫功能正常的宿主中。PVL被认为可诱导吞噬细胞的细胞溶解或凋亡。然而，最近对有或无PVL的同基因CA-MRSA菌株的比较显示，在人类中性粒细胞的细胞溶解活性方面并无差异。此外，迄今为止进行的许多小鼠研究未能证明PVL的毒力作用，从而引发了一个问题：PVL在人类感染中是否具有机制性作用？在本报告中，我们评估了PVL对严重皮肤和软组织感染的作用。我们在从坏死性筋膜炎患者分离出的CA-MRSA菌株中构建了PVL突变体，并使用这些工具评估PVL在体内的致病作用。在坏死性软组织感染模型中，我们发现PVL对肌肉造成了显著损伤，但对皮肤没有影响。肌肉损伤与促炎趋化因子KC、MIP-2和RANTES的诱导以及中性粒细胞的募集有关。组织损伤在年轻小鼠以及能更有效地清除金黄色葡萄球菌的小鼠品系中最为显著，而在对病原体免疫反应较有限的老年小鼠和小鼠品系中并不显著。PVL介导的损伤可通过抗PVL抗体预处理来阻断。我们的数据为CA-MRSA的发病机制、流行病学和治疗提供了新的见解。PVL可能导致CA-MRSA感染中肌炎发病率增加，并且该毒素可能通过直接杀死吞噬细胞以外的机制介导组织损伤。
