Division of Biotechnology Review and Research 1 (DBRR1), Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, MD 20993, USA.
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20814, USA.
Viruses. 2019 Sep 23;11(10):889. doi: 10.3390/v11100889.
Macrophages are one of the first and also a major site of filovirus replication and, in addition, are a source of multiple cytokines, presumed to play a critical role in the pathogenesis of the viral infection. Some of these cytokines are known to induce macrophage phenotypic changes in vitro, but how macrophage polarization may affect the cell susceptibility to filovirus entry remains largely unstudied. We generated different macrophage subsets using cytokine pre-treatment and subsequently tested their ability to fuse with beta-lactamase containing virus-like particles (VLP), pseudotyped with the surface glycoprotein of Ebola virus (EBOV) or the glycoproteins of other clinically relevant filovirus species. We found that pre-incubation of primary human monocyte-derived macrophages (MDM) with interleukin-10 (IL-10) significantly enhanced filovirus entry into cells obtained from multiple healthy donors, and the IL-10 effect was preserved in the presence of pro-inflammatory cytokines found to be elevated during EBOV disease. In contrast, fusion of IL-10-treated macrophages with influenza hemagglutinin/neuraminidase pseudotyped VLPs was unchanged or slightly reduced. Importantly, our in vitro data showing enhanced virus entry are consistent with the correlation established between elevated serum IL-10 and increased mortality in filovirus infected patients and also reveal a novel mechanism that may account for the IL-10-mediated increase in filovirus pathogenicity.
巨噬细胞是最早也是主要的丝状病毒复制部位之一，此外，还是多种细胞因子的来源，这些细胞因子被认为在病毒感染的发病机制中起关键作用。已知其中一些细胞因子可在体外诱导巨噬细胞表型改变，但巨噬细胞极化如何影响细胞对丝状病毒进入的易感性在很大程度上仍未得到研究。我们使用细胞因子预处理生成了不同的巨噬细胞亚群，然后测试了它们与含有β-内酰胺酶的病毒样颗粒（VLP）融合的能力，这些 VLP 假型化了埃博拉病毒（EBOV）或其他临床相关丝状病毒物种的表面糖蛋白。我们发现，用白细胞介素 10（IL-10）预处理原代人单核细胞衍生的巨噬细胞（MDM）可显著增强来自多个健康供体的细胞中丝状病毒的进入，并且在存在促炎细胞因子的情况下保留了 IL-10 效应，这些细胞因子在 EBOV 疾病期间被发现升高。相比之下，IL-10 处理的巨噬细胞与流感血凝素/神经氨酸酶假型化的 VLP 的融合没有改变或略有减少。重要的是，我们的体外数据显示增强的病毒进入与在丝状病毒感染患者中观察到的升高的血清 IL-10 和增加的死亡率之间建立的相关性一致，并且还揭示了一种可能解释 IL-10 介导的丝状病毒致病性增加的新机制。
