Human blood CD14⁺ monocytes are bone marrow–derived white blood cells that sense and respond to pathogens. Although innate immune activation by RNA viruses preferentially occurs through intracellular RIG-I–like receptors, other nucleic acid recognition receptors, such as Toll-like receptors (TLRs), play a role in finely programming the final outcome of virus infection. Here, we dissected how human monocytes respond to infection with either Coxsackie (CV), encephalomyocarditis (EMCV), influenza A (IAV), measles (MV), Sendai (SV), or vesicular stomatitis (VSV) virus. We found that in monocytes, type I interferon (IFN) and cytokine responses to infection were RNA virus specific and differentially involved TLR7 and TLR8, which sense single-stranded RNA. These TLRs activated distinct signaling cascades in monocytes, which correlated with differences in the production of cytokines involved in the polarization of CD4⁺ T helper cells. Furthermore, we found that TLR7 signaling specifically increased expression of the transcription factor FOSL1, which reduced IL-27 and TNFα production by monocytes. TLR7, but not TLR8, activation of monocytes also stimulated Ca²⁺ flux that prevented type I IFN responses. Our work demonstrates that in human monocytes, TLR7 and TLR8 triggered different signaling pathways that contribute to distinct phenotypes during RNA virus infection. In addition, we defined individual targets within these pathways that promoted specific T helper and antiviral responses.

人血CD14 ⁺单核细胞是源自骨髓的白细胞，可感知并响应病原体。尽管RNA病毒先天免疫激活优先通过细胞内RIG-I样受体发生，但其他核酸识别受体，如Toll样受体（TLR），在精确编程病毒感染的最终结果中发挥着作用。在这里，我们剖析了人类单核细胞对柯萨奇（CV），脑心肌炎（EMCV），甲型流感（IAV），麻疹（MV），仙台（SV）或水疱性口炎（VSV）病毒感染的反应。我们发现，在单核细胞中，I型干扰素（IFN）和细胞因子对感染的反应是RNA病毒特异性的，并且差异涉及TLR7和TLR8，后者可检测单链RNA。这些TLR激活了单核细胞中不同的信号传导级联，⁺ T辅助细胞。此外，我们发现TLR7信号特异性增加了转录因子FOSL1的表达，从而降低了单核细胞产生IL-27和TNFα的能力。TLR7（而不是TLR8）单核细胞的活化也刺激了阻止I型IFN反应的Ca ²⁺通量。我们的工作表明，在人类单核细胞中，TLR7和TLR8触发了不同的信号通路，这些信号通路在RNA病毒感染期间促成了不同的表型。此外，我们在这些途径中定义了可促进特定T辅助物和抗病毒反应的个体靶标。