Clinical and Experimental Sciences and NIHR Southampton Biomedical Research Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, LE59, MP813, SO16 6YD, Southampton, UK.
Caucaseco Scientific Research Center, Cali, 760043, Colombia; School of Health, Universidad del Valle, Cali, 76001, Colombia.
J Infect. 2018 Nov;77(5):440-447. doi: 10.1016/j.jinf.2018.09.005. Epub 2018 Sep 22.
To dissect the transcriptional networks underpinning immune cells responses during primary Plasmodium vivax infection of healthy human adults.
We conducted network co-expression analysis of next-generation RNA sequencing data from whole blood from P. vivax and P. falciparum controlled human malaria infection (CHMI) of healthy naïve and malaria-exposed volunteers. Single cell transcription signatures were used to deconvolute the bulk RNA-Seq data into cell-specific signals.
Initial exposure to P. vivax induced activation of innate immunity, including efficient antigen presentation and complement activation. However, this effect was accompanied by strong immunosuppression mediated by dendritic cells via the induction of Indoleamine 2,3-Dioxygenase 1(IDO1) and Lymphocyte Activation Gene 3 (LAG3). Additionally, P. vivax induced depletion of neutrophil populations associated with down regulation of 3G-protein coupled receptors, CRXCR1, CXCR2 and CSF3R. Accordingly, in malaria-exposed volunteers the inflammatory response was attenuated, with a decreased class II antigen presentation in dendritic cells. While the immunosuppressive signalling was maintained between plasmodium species, response to P. falciparum was significantly more immunogenic.
In silico analyses suggest that primary infection with P. vivax induces potent immunosuppression mediated by dendritic cells, conditioning subsequent anti-malarial immune responses. Targeting immune evasion mechanisms could be an effective alternative for improving vaccine efficacy.
剖析健康成年人初次感染间日疟原虫时免疫细胞反应的转录网络。
我们对来自健康初免和疟疾暴露志愿者的间日疟原虫和恶性疟原虫控制的人体疟疾感染（CHMI）全血的下一代 RNA 测序数据进行了网络共表达分析。单细胞转录特征用于将批量 RNA-Seq 数据分解为细胞特异性信号。
初次接触间日疟原虫诱导了先天免疫的激活，包括有效的抗原呈递和补体激活。然而，这种效应伴随着树突状细胞通过诱导吲哚胺 2,3-双加氧酶 1（IDO1）和淋巴细胞激活基因 3（LAG3）介导的强烈免疫抑制。此外，间日疟原虫诱导与 3G 蛋白偶联受体 CRXCR1、CXCR2 和 CSF3R 下调相关的中性粒细胞群耗竭。因此，在疟疾暴露的志愿者中，炎症反应减弱，树突状细胞中 II 类抗原呈递减少。虽然免疫抑制信号在疟原虫种间得以维持，但对恶性疟原虫的反应明显更具免疫原性。
计算机分析表明，初次感染间日疟原虫诱导树突状细胞介导的强烈免疫抑制，从而影响后续的抗疟免疫反应。针对免疫逃避机制可能是提高疫苗效力的有效替代方法。
