A privileged intraphagocyte niche is responsible for disseminated infection of Staphylococcus aureus in a zebrafish model.
A privileged intraphagocyte niche is responsible for disseminated infection of Staphylococcus aureus in a zebrafish model.
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DOI：
10.1111/j.1462-5822.2012.01826.x
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发表时间：
2012-10
影响因子：
3.4
通讯作者：
Renshaw SA
中科院分区：
文献类型：
--
作者：
Prajsnar TK;Hamilton R;Garcia-Lara J;McVicker G;Williams A;Boots M;Foster SJ;Renshaw SA
先天免疫系统是抵抗多功能病原体金黄色葡萄球菌的主要防御系统。这种微生物如何能够避免免疫杀伤并引起感染，目前还知之甚少。使用已建立的斑马鱼幼虫感染模型，我们已经表明，压倒性的感染是由于葡萄球菌吞噬细胞的颠覆，使细菌逃避杀死和发现疾病的病灶。斑马鱼幼鱼共感染两株S.携带不同荧光报道基因融合体（但在其它方面是同基因的）的金黄色葡萄球菌菌株在宿主死亡时具有细菌损伤，主要包含一种菌株。使用两种标记菌株的定量数据显示，在压倒性感染期间，菌株比率往往偏向极端，其中一种菌株占主导地位。用传代的细菌克隆感染表明，这种现象不是由于病原体获得的外源突变。在宿主感染后，所有的细菌都被吞噬细胞内化，并且种群比例的偏斜完全取决于吞噬细胞的存在。病原体种群动力学的数学模型显示，数据模式与少量感染的吞噬细胞作为S.金黄色葡萄球菌，其在释放时导致播散性感染。使用特异性改变中性粒细胞/巨噬细胞数量的策略来绘制充当病原体储库的吞噬细胞的潜在亚群，从而揭示中性粒细胞作为可能的“生态位”。随后在小鼠脓毒症模型中，S.还发现肾脏中的金黄色葡萄球菌感染主要是克隆性的，因此可能由单个细胞建立，这表明了类似于斑马鱼模型的潜在机制，几乎没有受保护的小生境。这些发现为S.金黄色葡萄球菌的控制方案应该识别S.金黄色葡萄球菌生命周期
The innate immune system is the primary defence against the versatile pathogen, Staphylococcus aureus. How this organism is able to avoid immune killing and cause infections is poorly understood. Using an established larval zebrafish infection model, we have shown that overwhelming infection is due to subversion of phagocytes by staphylococci, allowing bacteria to evade killing and found foci of disease. Larval zebrafish coinfected with two S. aureus strains carrying different fluorescent reporter gene fusions (but otherwise isogenic) had bacterial lesions, at the time of host death, containing predominantly one strain. Quantitative data using two marked strains revealed that the strain ratios, during overwhelming infection, were often skewed towards the extremes, with one strain predominating. Infection with passaged bacterial clones revealed the phenomenon not to bedue to adventitious mutations acquired by the pathogen. After infection of the host, all bacteria are internalized by phagocytes and the skewing of population ratios is absolutely dependent on the presence of phagocytes. Mathematical modelling of pathogen population dynamics revealed the data patterns are consistent with the hypothesis that a small number of infected phagocytes serve as an intracellular reservoir for S. aureus, which upon release leads to disseminated infection. Strategies to specifically alter neutrophil/macrophage numbers were used to map the potential subpopulation of phagocytes acting as a pathogen reservoir, revealing neutrophils as the likely ‘niche’. Subsequently in a murine sepsis model, S. aureus abscesses in kidneys were also found to be predominantly clonal, therefore likely founded by an individual cell, suggesting a potential mechanism analogous to the zebrafish model with few protected niches. These findings add credence to the argument that S. aureus control regimes should recognize both the intracellular as well as extracellular facets of the S. aureus life cycle.