Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.
PLoS Negl Trop Dis. 2012;6(12):e1966. doi: 10.1371/journal.pntd.0001966. Epub 2012 Dec 20.
Dengue is the most prevalent mosquito-borne human illness worldwide. The ability to predict disease severity during the earliest days of the illness is a long-sought, but unachieved goal.We examined human genome-wide transcript abundance patterns in daily peripheral blood mononuclear cell (PBMC) samples from 41 children hospitalized with dengue virus (DENV) infection in Nicaragua, as well as 8 healthy control subjects. Nine patients had primary dengue fever (DF1), 11 had dengue fever with serologic evidence of prior DENV infection, i.e., secondary dengue fever (DF2), 12 had dengue hemorrhagic fever (DHF), and 9 had dengue shock syndrome (DSS). We identified 2,092 genes for which transcript abundance differed significantly between patients on days 3-6 of fever and healthy subjects (FDR<1%). Prior DENV infection explained the greatest amount of variation in gene expression among patients. The number of differentially expressed genes was greatest on fever day 3 in patients with DF1, while the number in patients with DF2 or DHF/DSS was greatest on day 5. Genes associated with the mitotic cell cycle and B cell differentiation were expressed at higher levels, and genes associated with signal transduction and cell adhesion were expressed at lower levels, in patients versus healthy controls. On fever day 3, a set of interferon-stimulated gene transcripts was less abundant in patients who subsequently developed DSS than in other patient groups (p<0.05, ranksum). Patients who later developed DSS also had higher levels of transcripts on day 3 associated with mitochondrial function (p<0.01, ranksum). These day 3 transcript abundance findings were not evident on subsequent fever days.In conclusion, we identified differences in the timing and magnitude of human gene transcript abundance changes in DENV patients that were associated with serologic evidence of prior infection and with disease severity. Some of these differential features may predict the outcome of DENV infection.
登革热是全球最普遍的蚊媒传染病。能够在疾病早期预测疾病严重程度是一个长期以来的目标，但尚未实现。我们检测了来自尼加拉瓜 41 名登革热病毒（DENV）感染住院患儿以及 8 名健康对照者的外周血单个核细胞（PBMC）样本的全基因组转录丰度模式。9 名患者为原发性登革热（DF1），11 名患者为登革热，血清学证据显示之前感染过 DENV，即二次登革热（DF2），12 名患者为登革出血热（DHF），9 名患者为登革休克综合征（DSS）。我们鉴定了 2092 个基因，这些基因在发热后 3-6 天的患者与健康对照者之间的转录丰度差异显著（FDR<1%）。先前的 DENV 感染解释了患者之间基因表达变化的最大差异。在 DF1 患者中，差异表达基因的数量在发热第 3 天最大，而在 DF2 或 DHF/DSS 患者中，数量在发热第 5 天最大。与有丝分裂细胞周期和 B 细胞分化相关的基因表达水平较高，与信号转导和细胞黏附相关的基因表达水平较低，与健康对照组相比，患者的基因表达水平较高。在发热第 3 天，一组干扰素刺激的基因转录物在随后发生 DSS 的患者中比其他患者组（p<0.05，秩和检验）中更为稀少。在发热第 3 天，后来发生 DSS 的患者的转录本也与线粒体功能相关的转录本水平更高（p<0.01，秩和检验）。这些发热第 3 天的转录丰度发现，在随后的发热日并不明显。总之，我们发现了 DENV 患者中人类基因转录丰度变化的时间和幅度的差异，这些差异与先前感染的血清学证据和疾病严重程度有关。其中一些差异特征可能预测 DENV 感染的结果。
