Krebs Institute, University of Sheffield, Western Bank, Sheffield, UK.
Cell Microbiol. 2012 Oct;14(10):1600-19. doi: 10.1111/j.1462-5822.2012.01826.x. Epub 2012 Jul 4.
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.
先天免疫系统是抵御多面病原体金黄色葡萄球菌的主要防线。人们对该生物体如何能够避免免疫杀伤并引起感染知之甚少。使用已建立的幼虫斑马鱼感染模型，我们已经表明，压倒性感染是由于金黄色葡萄球菌对吞噬细胞的颠覆，使细菌能够逃避杀伤并找到疾病病灶。当宿主死亡时，同时感染两种带有不同荧光报告基因融合（但其他方面是同基因）的金黄色葡萄球菌菌株的幼虫斑马鱼会出现细菌病变，病变部位主要含有一种菌株。使用两种标记菌株的定量数据表明，在压倒性感染期间，菌株比例通常偏向极端，一种菌株占主导地位。感染经过传代的细菌克隆表明，这种现象不是病原体偶然获得的突变所致。感染宿主后，所有细菌都被吞噬细胞内化，种群比例的偏倚绝对取决于吞噬细胞的存在。对病原体种群动态的数学建模表明，数据模式与假设一致，即少数感染的吞噬细胞作为金黄色葡萄球菌的细胞内储库，一旦释放就会导致播散性感染。使用专门改变中性粒细胞/巨噬细胞数量的策略来绘制作为病原体储库的吞噬细胞的潜在亚群，结果表明中性粒细胞可能是“生态位”。随后在小鼠脓毒症模型中，还发现肾脏中的金黄色葡萄球菌脓肿主要是克隆的，因此可能是由单个细胞引起的，这表明存在一种类似于斑马鱼模型的潜在机制，即少数受保护的生态位。这些发现为金黄色葡萄球菌控制策略应认识到金黄色葡萄球菌生命周期的细胞内和细胞外方面提供了依据。
