RNA-Seq Analysis of the Host Response to Staphylococcus aureus Skin and Soft Tissue Infection in a Mouse Model
RNA-Seq Analysis of the Host Response to Staphylococcus aureus Skin and Soft Tissue Infection in a Mouse Model
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DOI：
10.1371/journal.pone.0124877
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发表时间：
2015-04-22
期刊：
影响因子：
3.7
通讯作者：
Burns, Drusilla L.
中科院分区：
文献类型：
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作者：
Brady, Rebecca A.;Bruno, Vincent M.;Burns, Drusilla L.
金黄色葡萄球菌是皮肤和软组织感染（SSTI）的主要原因，这主要是自限性的。我们对金黄色葡萄球菌SSTI期间的宿主转录组进行了全面分析，以提供对阻止这些感染的保护机制的见解。我们使用了一个小鼠SSTI模型，其中一只耳朵受到外源性挑战，而另一只耳朵没有。然后，我们在攻击后1、4和7天收集这些感染和未感染的耳朵，以及来自幼稚小鼠的耳朵，并使用Illumina平台进行RNA测序（RNA-seq）。RNA-seq数据显示在感染部位有很强的应答。比较攻毒小鼠的感染耳朵和未感染耳朵之间的基因表达谱定义了对感染的局部反应，而比较攻毒小鼠的未感染耳朵与幼稚小鼠的耳朵的表达谱则揭示了基因表达水平的变化，表明远离全身反应的部位。在所有测试时间点，超过1000个基因在局部表达增加。局部的反应比系统的反应更有力。通过使用Upstream Regulator Analysis （Ingenuity Pathway Analysis软件包的一部分）对RNA-seq数据进行评估，我们发现调控通路的激活和抑制的变化首先发生在局部，而滞后于系统。在SSTI期间的所有三个时间点，激活的通路高度相似，表明随着时间的推移，全球反应稳定。转录增加和通路激活涉及促炎性和抗炎介质、趋化性、细胞信号传导、角蛋白和TH1/TH17细胞因子。转录减少和途径抑制表明代谢基因和抗炎途径受到抑制。这些数据提供了对宿主反应的见解，可能有助于解决这种自限性金黄色葡萄球菌感染，并可能阐明葡萄球菌性SSTI保护的潜在免疫相关因素。
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 naive 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 naive 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.