Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.
Orthopaedic Biomechanics, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, Netherlands.
Front Cell Infect Microbiol. 2023 Jan 31;13:1013842. doi: 10.3389/fcimb.2023.1013842. eCollection 2023.
Macrophages are amongst the first immune cells that encounter rabies virus (RABV) at virus entry sites. Activation of macrophages is essential for the onset of a potent immune response, but insights into the effects of RABV on macrophage activation are scarce. In this study we performed high-throughput sequencing on RNA extracted from macrophages that were exposed to RABV for 48 hours, and compared their transcriptional profiles to that of non-polarized macrophages (M0), and macrophages polarized towards the canonical M1, M2a and M2c phenotypes. Our analysis revealed that RABV-stimulated macrophages show high expression of several M1, M2a and M2c signature genes. Apart from their partial resemblance to these phenotypes, unbiased clustering analysis revealed that RABV induces a unique and distinct polarization program. Closer examination revealed that RABV induced multiple pathways related to the interferon- and antiviral response, which were not induced under other classical polarization strategies. Surprisingly, our data show that RABV induces an activated rather than a fully suppressed macrophage phenotype, triggering virus-induced activation and polarization. This includes multiple genes with known antiviral (e.g. APOBEC3A, IFIT/OAS/TRIM genes), which may play a role in anti-RABV immunity.
巨噬细胞是在病毒进入部位首先遇到狂犬病病毒 (RABV) 的免疫细胞之一。巨噬细胞的激活对于引发有效的免疫反应至关重要，但对 RABV 对巨噬细胞激活的影响的了解甚少。在这项研究中，我们对暴露于 RABV 48 小时的巨噬细胞提取的 RNA 进行了高通量测序，并将其转录谱与非极化巨噬细胞 (M0) 以及极化到经典 M1、M2a 和 M2c 表型的巨噬细胞进行了比较。我们的分析表明，RABV 刺激的巨噬细胞表现出几种 M1、M2a 和 M2c 特征基因的高表达。除了与这些表型有部分相似之处外，无偏聚类分析还表明，RABV 诱导了一种独特而不同的极化程序。进一步研究表明，RABV 诱导了与干扰素和抗病毒反应相关的多个途径，而这些途径在其他经典极化策略下不会被诱导。令人惊讶的是，我们的数据表明，RABV 诱导了一种激活而不是完全抑制的巨噬细胞表型，引发病毒诱导的激活和极化。这包括多个具有已知抗病毒作用的基因（例如 APOBEC3A、IFIT/OAS/TRIM 基因），它们可能在抗 RABV 免疫中发挥作用。
