Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria.
Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria.
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DOI：
10.1126/scitranslmed.aar3619
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发表时间：
2018-06-27
影响因子：
17.1
通讯作者：
Cunnington AJ
中科院分区：
文献类型：
--
作者：
Lee HJ;Georgiadou A;Walther M;Nwakanma D;Stewart LB;Levin M;Otto TD;Conway DJ;Coin LJ;Cunnington AJ
传染病的发病机制依赖于宿主和病原体的相互作用。在恶性疟疾中，宿主和寄生虫的过程可以通过对感染患者的血液进行双重RNA测序来评估。在这里，我们对46名感染疟疾的冈比亚儿童的样本进行了双重转录组分析，以揭示驱动严重疟疾系统病理生理学的机制。将这些转录数据与寄生虫载量的估计和详细的临床信息相结合，可以考虑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产生的潜在混杂效应。我们报告了数百个人类和寄生虫基因在严重和简单疟疾之间的差异表达，与昏迷、高乳酸血症和血小板减少相关的不同特征。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相关。我们观察到寄生虫基因的表达与严重程度相关，这些基因决定了细胞对血管内皮细胞的黏附、感染红细胞的刚性和寄生虫的生长速度。在严重疟疾中，高达99%的人类差异基因表达是由寄生虫载量的差异驱动的，而寄生虫基因表达与寄生虫载量几乎没有关联。共表达分析揭示了人和恶性疟原虫之间的相互作用，在严重疟疾宿主和寄生虫之间存在显著的翻译基因共同调节。多变量分析表明，粒细胞和干扰素-γ相关基因的表达增加，加上对1型干扰素信号的抑制不足，最好地解释了感染的严重程度。这些发现为了解宿主和寄生虫在严重疟疾发病机制中的作用和确定辅助治疗的目标提供了一个框架。
The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In Plasmodium falciparum malaria, host and parasite processes can be assessed by dual RNA-sequencing of blood from infected patients. Here 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. Co-expression analyses revealed interactions between human and P. falciparum, 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 signalling, 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 targets for adjunctive therapy.
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影响因子：
6.4
作者：
Dietmann, Anelia;Helbok, Raimund;Kremsner, Peter G.
通讯作者：
Kremsner, Peter G.
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1001/jama.2016.0136
发表时间：
2016-02-23
期刊：
JAMA
影响因子：
--
作者：
Alhamdi Y;Abrams ST;Lane S;Wang G;Toh CH
通讯作者：
Toh CH
影响因子：
6.5
作者：
Cooke, BM;Glenister, FK;Coppel, RL
通讯作者：
Coppel, RL
影响因子：
28.2
作者：
Cunnington, Aubrey J.;Bretscher, Michael T.;Nogaro, Sarah I.;Riley, Eleanor M.;Walther, Michael
通讯作者：
Walther, Michael