Brady Rebecca A, Bruno Vincent M, Burns Drusilla L
Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, United States of America.
Institute for Genome Sciences, University of Maryland Baltimore, Baltimore, Maryland, United States of America.
PLoS One. 2015 Apr 22;10(4):e0124877. doi: 10.1371/journal.pone.0124877. eCollection 2015.
Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTI), which are primarily self-limiting. We conducted a comprehensive analysis of the host transcriptome during a S. aureus SSTI to provide insight on the protective mechanisms that thwart these infections. We utilized a murine SSTI model in which one ear is epicutaneously challenged while the other is not. We then harvested these infected and uninfected ears, as well as ears from naïve mice, at one, four, and seven days post-challenge, and performed RNA sequencing (RNA-seq) using the Illumina platform. RNA-seq data demonstrated a robust response at the site of infection. Comparison of gene expression profiles between infected ears and the non-infected ears of challenged mice defined the local response to infection, while comparisons of expression profiles of non-infected ears from challenged mice to ears of naïve mice revealed changes in gene expression levels away from the site indicative of a systemic response. Over 1000 genes exhibited increased expression locally at all tested time points. The local response was more robust than the systemic response. Through evaluation of the RNA-seq data using the Upstream Regulator Analytic as part of the Ingenuity Pathway Analysis software package, we found that changes in the activation and inhibition of regulatory pathways happen first locally, and lag behind systemically. The activated pathways are highly similar at all three time points during SSTI, suggesting a stable global response over time. Transcript increases and pathway activation involve pro- and anti-inflammatory mediators, chemotaxis, cell signaling, keratins, and TH1/TH17 cytokines. Transcript decreases and pathway inhibition demonstrate that metabolic genes and anti-inflammatory pathways are repressed. These data provide insight on the host responses that may aid in resolution of this self-limited S. aureus infection, and may shed light on potential immune correlates of protection for staphylococcal SSTI.
金黄色葡萄球菌是皮肤和软组织感染（SSTI）的主要病因，这些感染大多为自限性。我们对金黄色葡萄球菌引起的SSTI期间的宿主转录组进行了全面分析，以深入了解抵御这些感染的保护机制。我们使用了一种小鼠SSTI模型，其中一只耳朵经皮接种，而另一只耳朵不接种。然后，在接种后1天、4天和7天收集这些感染和未感染的耳朵以及未接触过病原体的小鼠的耳朵，并使用Illumina平台进行RNA测序（RNA-seq）。RNA-seq数据显示感染部位有强烈反应。比较接种小鼠感染耳朵和未感染耳朵之间的基因表达谱，确定了对感染的局部反应，而将接种小鼠未感染耳朵的表达谱与未接触过病原体的小鼠耳朵的表达谱进行比较，则揭示了远离感染部位的基因表达水平变化，这表明存在全身反应。超过1000个基因在所有测试时间点局部表达均增加。局部反应比全身反应更强烈。通过使用上游调节因子分析（作为Ingenuity Pathway Analysis软件包的一部分）评估RNA-seq数据，我们发现调节通路的激活和抑制变化首先在局部发生，而全身变化则滞后。在SSTI的所有三个时间点，激活的通路高度相似，表明随着时间的推移存在稳定的整体反应。转录本增加和通路激活涉及促炎和抗炎介质、趋化作用、细胞信号传导、角蛋白以及TH1/TH17细胞因子。转录本减少和通路抑制表明代谢基因和抗炎通路受到抑制。这些数据深入了解了可能有助于解决这种自限性金黄色葡萄球菌感染的宿主反应，并可能揭示葡萄球菌SSTI潜在的免疫保护相关因素。
