Sampaio Natália Guimarães, Eriksson Emily Marie, Schofield Louis
Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Infect Immun. 2017 Dec 19;86(1). doi: 10.1128/IAI.00447-17. Print 2018 Jan.
Immunity to malaria is slow to develop, and it is often asserted that malaria suppresses host immunity, although this is poorly understood and the molecular basis for such activity remains unknown. erythrocyte membrane protein 1 (PfEMP1) is a virulence factor that plays a key role in parasite-host interactions. We investigated the immunosuppressive effect of PfEMP1 on monocytes/macrophages, which are central to the antiparasitic innate response. RAW macrophages and human primary monocytes were stimulated with wild-type 3D7 or CS2 parasites or transgenic PfEMP1-null parasites. To study the immunomodulatory effect of PfEMP1, transcription factor activation and cytokine and chemokine responses were measured. The level of activation of NF-κB was significantly lower in macrophages stimulated with parasites that express PfEMP1 at the red blood cell surface membrane than in macrophages stimulated with PfEMP1-null parasites. Modulation of additional transcription factors, including CREB, also occurred, resulting in reduced immune gene expression and decreased tumor necrosis factor (TNF) and interleukin-10 (IL-10) release. Similarly, human monocytes released less IL-1β, IL-6, IL-10, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and TNF specifically in response to VAR2CSA PfEMP1-containing parasites than in response to PfEMP1-null parasites, suggesting that this immune regulation by PfEMP1 is important in naturally occurring infections. These results indicate that PfEMP1 is an immunomodulatory molecule that affects the activation of a range of transcription factors, dampening cytokine and chemokine responses. Therefore, these findings describe a potential molecular basis for immune suppression by .
对疟疾的免疫力发展缓慢，人们常认为疟疾会抑制宿主免疫力，尽管对此了解甚少，且这种活性的分子基础仍不清楚。红细胞膜蛋白1（PfEMP1）是一种毒力因子，在寄生虫与宿主的相互作用中起关键作用。我们研究了PfEMP1对单核细胞/巨噬细胞的免疫抑制作用，单核细胞/巨噬细胞在抗寄生虫固有反应中起核心作用。用野生型3D7或CS2寄生虫或转基因PfEMP1缺失寄生虫刺激RAW巨噬细胞和人原代单核细胞。为了研究PfEMP1的免疫调节作用，测量了转录因子激活以及细胞因子和趋化因子反应。与用PfEMP1缺失寄生虫刺激的巨噬细胞相比，在用红细胞表面膜表达PfEMP1的寄生虫刺激的巨噬细胞中，NF-κB的激活水平显著降低。包括CREB在内的其他转录因子也发生了调节，导致免疫基因表达减少以及肿瘤坏死因子（TNF）和白细胞介素-10（IL-10）释放减少。同样，与对PfEMP1缺失寄生虫的反应相比，人单核细胞在对含VAR2CSA PfEMP1的寄生虫的特异性反应中释放的IL-1β、IL-6、IL-10、单核细胞趋化蛋白1（MCP-1）、巨噬细胞炎性蛋白1α（MIP-1α）、MIP-1β和TNF更少，这表明PfEMP1的这种免疫调节在自然发生的感染中很重要。这些结果表明，PfEMP1是一种免疫调节分子，可影响一系列转录因子的激活，抑制细胞因子和趋化因子反应。因此，这些发现描述了疟原虫免疫抑制的潜在分子基础。
