Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Section of Paediatrics, Imperial College, London W2 1PG, UK.
Sci Transl Med. 2018 Jun 27;10(447). doi: 10.1126/scitranslmed.aar3619.
The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In malaria, host and parasite processes can be assessed by dual RNA sequencing of blood from infected patients. We performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria. Integrating these transcriptomic data with estimates of parasite load and detailed clinical information allowed consideration of potentially confounding effects due to differing leukocyte proportions in blood, parasite developmental stage, and whole-body pathogen load. We report hundreds of human and parasite genes differentially expressed between severe and uncomplicated malaria, with distinct profiles associated with coma, hyperlactatemia, and thrombocytopenia. High expression of neutrophil granule-related genes was consistently associated with all severe malaria phenotypes. We observed severity-associated variation in the expression of parasite genes, which determine cytoadhesion to vascular endothelium, rigidity of infected erythrocytes, and parasite growth rate. Up to 99% of human differential gene expression in severe malaria was driven by differences in parasite load, whereas parasite gene expression showed little association with parasite load. Coexpression analyses revealed interactions between human and , with prominent co-regulation of translation genes in severe malaria between host and parasite. Multivariate analyses suggested that increased expression of granulopoiesis and interferon-γ-related genes, together with inadequate suppression of type 1 interferon signaling, best explained severity of infection. These findings provide a framework for understanding the contributions of host and parasite to the pathogenesis of severe malaria and identifying new treatments.
传染病的发病机制取决于宿主和病原体的相互作用。在疟疾中，可以通过对感染患者的血液进行双 RNA 测序来评估宿主和寄生虫的过程。我们对来自 46 名感染疟疾的冈比亚儿童的样本进行了双转录组分析，以揭示导致严重疟疾全身病理生理学的机制。将这些转录组数据与寄生虫载量的估计值和详细的临床信息相结合，考虑了由于血液中白细胞比例、寄生虫发育阶段和全身病原体载量的不同而可能产生的混杂影响。我们报告了数百个人类和寄生虫基因在严重和不复杂的疟疾之间表达差异，与昏迷、高乳酸血症和血小板减少症相关的特征性特征。中性粒细胞颗粒相关基因的高表达与所有严重疟疾表型一致。我们观察到与寄生虫基因表达相关的严重程度变化，这些基因决定了寄生虫对血管内皮的细胞粘附、感染红细胞的刚性和寄生虫的生长速度。高达 99%的人类严重疟疾差异基因表达是由寄生虫载量差异驱动的，而寄生虫基因表达与寄生虫载量几乎没有关联。共表达分析揭示了宿主和寄生虫之间的相互作用，在严重疟疾中，宿主和寄生虫之间的翻译基因存在明显的共调控。多变量分析表明，粒细胞生成和干扰素-γ相关基因的表达增加，加上 1 型干扰素信号的不足抑制，最能解释感染的严重程度。这些发现为理解宿主和寄生虫对严重疟疾发病机制的贡献以及确定新的治疗方法提供了框架。
