PDF(Pubmed)
Abstract：
Malaria transmission and endemicity in Africa remains hugely disproportionate compared to the rest of the world. The complex life cycle of P. falciparum (Pf) between the vertebrate human host and the anopheline vector results in differential expression of genes within and between hosts. An in-depth understanding of Pf interaction with various human genes through regulatory elements will pave way for identification of newer tools in the arsenal for malaria control. Therefore, the regulatory elements (REs) involved in the over- or under-expression of various host immune genes hold the key to elucidating alternative control measures that can be applied for disease surveillance, prompt diagnosis and treatment. We carried out an RNAseq analysis to identify differentially expressed genes and network elucidation of non-coding RNAs and target genes associated with immune response in individuals with different clinical outcomes. Raw RNAseq datasets, retrieved for analyses include individuals with severe (Gambia-20), symptomatic (Burkina Faso-15), asymptomatic (Mali-16) malaria as well as uninfected controls (Tanzania-20; Mali-36). Of the total 107 datasets retrieved, we identified 5534 differentially expressed genes (DEGs) among disease and control groups. A peculiar pattern of DEGs was observed, with individuals presenting with severe/symptomatic malaria having the highest and most diverse upregulated genes, while a reverse phenomenon was recorded among asymptomatic and uninfected individuals. In addition, we identified 141 differentially expressed micro RNA (miRNA), of which 78 and 63 were upregulated and downregulated respectively. Interactome analysis revealed a moderate interaction between DEGs and miRNAs. Of all identified miRNA, five were unique (hsa-mir-32, hsa-mir-25, hsa-mir-221, hsa-mir-29 and hsa-mir-148) because of their connectivity to several genes, including hsa-mir-221 connected to 16 genes. Six-hundred and eight differentially expressed long non coding RNA (lncRNA) were also identified, including SLC7A11, LINC01524 among the upregulated ones. Our study provides important insight into host immune genes undergoing differential expression under different malaria conditions. It also identified unique miRNAs and lncRNAs that modify and/or regulate the expression of various immune genes. These regulatory elements we surmise, have the potential to serve a diagnostic purpose in discriminating between individuals with severe/symptomatic malaria and those with asymptomatic infection or uninfected, following further clinical validation from field isolates.
摘要：
与世界其他地区相比，非洲的疟疾传播和地方病仍然不成比例。脊椎动物人类宿主和按蚊载体之间恶性疟原虫（Pf）的复杂生命周期导致宿主内部和宿主之间基因的差异表达。通过调控元件深入了解Pf与各种人类基因的相互作用将为识别疟疾控制武器库中的新工具铺平道路。因此,参与各种宿主免疫基因过度表达或表达不足的调控元件（REs）是阐明可用于疾病监测的替代控制措施的关键，及时诊断和治疗。我们进行了RNAseq分析，以鉴定不同临床结果的个体中与免疫应答相关的非编码RNA和靶基因的差异表达基因和网络阐明。原始RNAseq数据集，检索用于分析的包括患有严重疾病的个体(冈比亚-20)，症状（布基纳法索-15），无症状（马里-16）疟疾以及未感染的控制（坦桑尼亚-20；马里-36）。在总共检索到的107个数据集中，我们在疾病组和对照组中鉴定了5534个差异表达基因(DEGs).观察到一种特殊的DEG模式，患有严重/有症状的疟疾的个体具有最高和最多样化的上调基因，而在无症状和未感染的个体中记录了相反的现象。此外,我们鉴定了141个差异表达的微小RNA（miRNA），其中78和63分别上调和下调。相互作用组分析揭示了DEGs和miRNAs之间的适度相互作用。在所有鉴定的miRNA中，五个是独特的(hsa-mir-32、hsa-mir-25、hsa-mir-221、hsa-mir-29和hsa-mir-148)，因为它们与几个基因相连，包括连接到16个基因的hsa-mir-221。还鉴定了六百八种差异表达的长链非编码RNA（lncRNA），其中包括SLC7A11、LINC01524。我们的研究为在不同疟疾条件下发生差异表达的宿主免疫基因提供了重要见解。它还鉴定了修饰和/或调节各种免疫基因表达的独特miRNA和lncRNA。我们推测这些监管要素，有可能在区分严重/有症状的疟疾患者和无症状感染或未感染的患者方面起到诊断作用，在现场分离株的进一步临床验证之后。
