Howard Hughes Medical Institute, New Haven, CT, USA.
Department of Immunobiology, Yale University, New Haven, CT, USA.
Nat Microbiol. 2018 May;3(5):611-621. doi: 10.1038/s41564-018-0138-2. Epub 2018 Apr 9.
Antibiotics are widely used to treat infections in humans. However, the impact of antibiotic use on host cells is understudied. Here we identify an antiviral effect of commonly used aminoglycoside antibiotics. We show that topical mucosal application of aminoglycosides prophylactically increased host resistance to a broad range of viral infections including herpes simplex viruses, influenza A virus and Zika virus. Aminoglycoside treatment also reduced viral replication in primary human cells. This antiviral activity was independent of the microbiota, because aminoglycoside treatment protected germ-free mice. Microarray analysis uncovered a marked upregulation of transcripts for interferon-stimulated genes (ISGs) following aminoglycoside application. ISG induction was mediated by Toll-like receptor 3, and required Toll/interleukin-1-receptor-domain-containing adapter-inducing interferon-β signalling adaptor, and Interferon regulatory factors 3 and 7, transcription factors that promote ISG expression. XCR1 dendritic cells, which uniquely express Toll-like receptor 3, were recruited to the vaginal mucosa upon aminoglycoside treatment and were required for ISG induction. These results highlight an unexpected ability of aminoglycoside antibiotics to confer broad antiviral resistance in vivo.
抗生素被广泛用于治疗人类感染。然而，抗生素使用对宿主细胞的影响还研究得不够充分。在这里，我们确定了常用氨基糖苷类抗生素的抗病毒作用。我们发现，局部黏膜应用氨基糖苷类抗生素可预防性地提高宿主对包括单纯疱疹病毒、甲型流感病毒和寨卡病毒在内的多种病毒感染的抵抗力。氨基糖苷类药物治疗还减少了原代人细胞中的病毒复制。这种抗病毒活性与微生物群无关，因为氨基糖苷类药物治疗可以保护无菌小鼠。微阵列分析发现，氨基糖苷类药物应用后干扰素刺激基因 (ISG) 的转录物明显上调。ISG 诱导由 Toll 样受体 3 介导，需要 Toll/白细胞介素-1-受体结构域包含衔接诱导干扰素-β信号转导衔接子，以及转录因子干扰素调节因子 3 和 7，它们促进 ISG 表达。XCR1 树突状细胞在阴道黏膜中表达独特的 Toll 样受体 3，在氨基糖苷类药物治疗后被招募到阴道黏膜中，并且是 ISG 诱导所必需的。这些结果突出了氨基糖苷类抗生素在体内赋予广泛抗病毒抗性的意外能力。
