Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, Heidelberg, Germany.
PLoS One. 2018 Jun 19;13(6):e0198555. doi: 10.1371/journal.pone.0198555. eCollection 2018.
Sepsis is defined as a life-threatening condition, resulting from a dysregulated and harmful response of the hosts' immune system to infection. Apart from this, the (over-)compensating mechanisms counterbalancing the inflammatory response have been proven to render the host susceptible to further infections and increase delayed mortality. Our study aimed to unravel the heterogeneity of immune response in early sepsis and to explain the biology behind it.
A systematic search of public repositories yielded 949 microarray samples from patients with sepsis of different infectious origin and early after clinical manifestation. These were merged into a meta-expression set, and after applying sequential conservative bioinformatics filtering, an in-deep analysis of transcriptional heterogeneity, as well as a comparison to samples of healthy controls was performed.
We can identify two distinct clusters of patients (cluster 1: 655 subjects, cluster 2: 294 subjects) according to their global blood transcriptome. While both clusters exhibit only moderate differences in direct comparison, a comparison of both clusters individually to healthy controls yielded strong expression changes of genes involved in immune responses. Both comparisons found similar regulated genes, with a stronger dysregulation occurring in the larger patient cluster and implicating a loss of monocyte and T cell function, co-occurring with an activation of neutrophil granulocytes.
We propose a consistent-but in its extent varying-presence of immunosuppression, occurring as early in sepsis as its clinical manifestation and irrespective of the infectious origin. While certain cell types possess contradictory activation states, our finding underlines the urgent need for an early host-directed therapy of sepsis side-by-side with antibiotics.
败血症是一种危及生命的疾病，是由宿主免疫系统对感染的失调和有害反应引起的。除此之外，已证明代偿性机制会抵消炎症反应，使宿主易受进一步感染，并增加延迟性死亡率。我们的研究旨在阐明早期败血症免疫反应的异质性，并解释其背后的生物学机制。
系统地搜索公共数据库，从不同感染源和临床症状出现后早期的败血症患者中获得了 949 个微阵列样本。这些样本被合并成一个元表达集，然后应用顺序保守的生物信息学过滤方法，对转录组异质性进行深入分析，并与健康对照样本进行比较。
根据他们的全血转录组，我们可以将患者分为两个不同的聚类（聚类 1：655 例，聚类 2：294 例）。虽然这两个聚类在直接比较中只有中度差异，但将这两个聚类分别与健康对照组进行比较，发现与免疫反应相关的基因表达发生了强烈变化。两种比较都发现了相似的调节基因，较大的患者聚类中发生了更强的失调，暗示单核细胞和 T 细胞功能丧失，同时中性粒细胞被激活。
我们提出了一种一致但程度不同的免疫抑制存在的假说，这种抑制存在于败血症的临床表现之前，并与感染源无关。虽然某些细胞类型存在矛盾的激活状态，但我们的发现强调了在抗生素治疗败血症的同时，急需进行早期宿主导向治疗。
