OBJECTIVES Malaria, caused by Plasmodium infection, remains a major global health problem. Monocytes are integral to the immune response, yet their transcriptional and functional responses in primary Plasmodium falciparum infection and in clinical malaria are poorly understood. METHODS The transcriptional and functional profiles of monocytes were examined in controlled human malaria infection with P. falciparum blood stages and in children and adults with acute malaria. Monocyte gene expression and functional phenotypes were examined by RNA sequencing and flow cytometry at peak infection and compared to pre-infection or at convalescence in acute malaria. RESULTS In subpatent primary infection, the monocyte transcriptional profile was dominated by an interferon (IFN) molecular signature. Pathways enriched included type I IFN signalling, innate immune response and cytokine-mediated signalling. Monocytes increased TNF and IL-12 production upon in vitro toll-like receptor stimulation and increased IL-10 production upon in vitro parasite restimulation. Longitudinal phenotypic analyses revealed sustained significant changes in the composition of monocytes following infection, with increased CD14+CD16- and decreased CD14-CD16+ subsets. In acute malaria, monocyte CD64/FcγRI expression was significantly increased in children and adults, while HLA-DR remained stable. Although children and adults showed a similar pattern of differentially expressed genes, the number and magnitude of gene expression change were greater in children. CONCLUSIONS Monocyte activation during subpatent malaria is driven by an IFN molecular signature with robust activation of genes enriched in pathogen detection, phagocytosis, antimicrobial activity and antigen presentation. The greater magnitude of transcriptional changes in children with acute malaria suggests monocyte phenotypes may change with age or exposure.

中文翻译：

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转录谱分析和免疫表型分析显示在亚专利恶性疟原虫感染中血液单核细胞持续激活。

目标 由疟原虫感染引起的疟疾仍然是一个主要的全球健康问题。单核细胞是免疫反应不可或缺的组成部分，但对它们在原发性恶性疟原虫感染和临床疟疾中的转录和功能反应知之甚少。方法 在具有恶性疟原虫血期的受控人类疟疾感染以及患有急性疟疾的儿童和成人中检查单核细胞的转录和功能概况。在感染高峰期通过 RNA 测序和流式细胞术检查单核细胞基因表达和功能表型，并与急性疟疾感染前或恢复期进行比较。结果 在亚专利原发性感染中，单核细胞转录谱由干扰素 (IFN) 分子特征主导。丰富的途径包括 I 型 IFN 信号，先天免疫反应和细胞因子介导的信号传导。单核细胞在体外 toll 样受体刺激后增加了 TNF 和 IL-12 的产生，在体外寄生虫再刺激后增加了 IL-10 的产生。纵向表型分析显示感染后单核细胞的组成持续发生显着变化，CD14+CD16- 亚群增加，CD14-CD16+ 亚群减少。在急性疟疾中，儿童和成人的单核细胞 CD64/FcγRI 表达显着增加，而 HLA-DR 保持稳定。尽管儿童和成人表现出相似的差异表达基因模式，但儿童基因表达变化的数量和幅度更大。结论 潜伏性疟疾期间的单核细胞激活是由 IFN 分子特征驱动的，具有强大的激活丰富的病原体检测基因，吞噬作用、抗菌活性和抗原呈递。患有急性疟疾的儿童的转录变化幅度更大，这表明单核细胞表型可能会随着年龄或暴露而变化。