Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria
Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria
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DOI：
10.1172/jci.insight.95352
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发表时间：
2017-09-01
期刊：
影响因子：
8
通讯作者：
Dent, Arlene E.
中科院分区：
文献类型：
--
作者：
Dobbs, Katherine R.;Embury, Paula;Dent, Arlene E.
背景。炎症和单核细胞被认为是人类疟疾发病的重要因素。然而，在疟疾流行人群中，炎症和各种单核细胞功能与急性疟疾、急性疟疾康复和无症状寄生虫病之间的关系尚不清楚。我们评估了1- 10岁肯尼亚儿童的血浆细胞因子水平、单核细胞亚群、单核细胞功能反应和单核细胞炎症转录谱，这些儿童在急性无并发症疟疾发病时和6周后康复时进行了研究。这些结果与来自同一社区无症状儿童和成人的类似数据进行了比较。急性疟疾的特点是促炎和调节性细胞因子水平升高，炎症“中间”单核细胞亚群扩大，6周后恢复到健康无症状儿童的水平。单核细胞在急性疟疾期间表现出活化的表型，对先天免疫和适应性免疫重要的标记物的表面表达发生变化。功能上，急性疟疾单核细胞和来自无症状感染儿童的单核细胞相对于无血期感染的无症状儿童，对恶性疟原虫感染红细胞的吞噬功能受损。来自急性疟疾和恢复时间点的单核细胞对先天免疫激动剂表现出强烈而等效的细胞因子反应，与感染状态无关。单核细胞转录谱显示，与疟疾初期单核细胞不同，促炎和抗炎基因表达模式受到调节和平衡，吞噬基因表达模式发生改变。这些观察结果提供了对单核细胞功能和先天免疫反应在无并发症疟疾期间的见解，并表明儿童无症状寄生虫病在临床上不是良性的。这项工作由美国国立卫生研究院/国家过敏和传染病研究所（R01AI095192-05）、Burroughs Wellcome基金/美国热带医学和卫生学会以及彩虹婴儿和儿童基金会提供支持。
BACKGROUND. Inflammation and monocytes are thought to be important to human malaria pathogenesis. However, the relationship of inflammation and various monocyte functions to acute malaria, recovery from acute malaria, and asymptomatic parasitemia in endemic populations is poorly understood.METHODS. We evaluated plasma cytokine levels, monocyte subsets, monocyte functional responses, and monocyte inflammatory transcriptional profiles of 1- to 10-year-old Kenyan children at the time of presentation with acute uncomplicated malaria and at recovery 6 weeks later; these results were compared with analogous data from asymptomatic children and adults in the same community.RESULTS. Acute malaria was marked by elevated levels of proinflammatory and regulatory cytokines and expansion of the inflammatory "intermediate" monocyte subset that returned to levels of healthy asymptomatic children 6 weeks later. Monocytes displayed activated phenotypes during acute malaria, with changes in surface expression of markers important to innate and adaptive immunity. Functionally, acute malaria monocytes and monocytes from asymptomatic infected children had impaired phagocytosis of P. falciparum-infected erythrocytes relative to asymptomatic children with no blood-stage infection. Monocytes from both acute malaria and recovery time points displayed strong and equivalent cytokine responsiveness to innate immune agonists that were independent of infection status. Monocyte transcriptional profiles revealed regulated and balanced proinflammatory and antiinflammatory and altered phagocytosis gene expression patterns distinct from malaria-naive monocytes.CONCLUSION. These observations provide insights into monocyte functions and the innate immune response during uncomplicated malaria and suggest that asymptomatic parasitemia in children is not clinically benign.FUNDING. Support for this work was provided by NIH/National Institute of Allergy and Infectious Diseases (R01AI095192-05), the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene, and the Rainbow Babies & Children's Foundation.