State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University.
Jiangsu Key Laboratory of Molecular Medicine.
Am J Respir Cell Mol Biol. 2022 Aug;67(2):227-240. doi: 10.1165/rcmb.2021-0362OC.
Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections in infants and young children. Axl, a TAM family receptor tyrosine kinase, has been demonstrated to be a receptor mediating enveloped virus infection. Here we show that Axl functions as a suppressor of antiviral response during RSV infection. Knockdown of Axl expression in human cells resulted in cell resistance to RSV infection, although the treatment did not significantly affect RSV binding or cell entry. Mice deficient in showed resistance to RSV infection, including reduction in viral load and in pulmonary injury. Although T lymphocyte and macrophage infiltration was reduced, more IFN-γ-producing cells were present in BAL fluid in mice. Fewer alternatively activated alveolar macrophages were found in the lungs of mice. mouse embryonic fibroblasts and siRNA-treated human cells had more robust IFN-β and IFN-stimulated gene induction of antiviral genes. Furthermore, reexpression of Axl using adenovirus-mediated Axl delivery repressed IFN-stimulated gene induction in Axl-null mouse embryonic fibroblasts by RSV infection. The results suggest that Axl, independent of being a virus entry receptor of RSV infection, negatively regulates IFN signaling to modulate host antiviral response against RSV infection.
呼吸道合胞病毒（RSV）是导致婴儿和幼儿严重下呼吸道感染的主要原因。AXL 是一种 TAM 家族受体酪氨酸激酶，已被证明是一种介导包膜病毒感染的受体。在这里，我们发现 AXL 在 RSV 感染期间作为抗病毒反应的抑制剂发挥作用。在人类细胞中敲低 AXL 的表达会导致细胞对 RSV 感染产生抗性，尽管该处理不会显著影响 RSV 结合或细胞进入。 缺失的小鼠对 RSV 感染具有抗性，包括降低病毒载量和肺损伤。虽然 T 淋巴细胞和巨噬细胞浸润减少，但 在 BAL 液中存在更多产生 IFN-γ 的细胞。在 缺失的小鼠肺部发现的交替激活的肺泡巨噬细胞较少。 缺失的小鼠胚胎成纤维细胞和经 siRNA 处理的人细胞具有更强的 IFN-β 和 IFN 刺激基因诱导抗病毒基因的能力。此外，通过 RSV 感染用腺病毒介导的 AXL 传递再表达 AXL 会抑制 AXL 缺失的小鼠胚胎成纤维细胞中 IFN 刺激基因的诱导。结果表明，AXL 独立于 RSV 感染的病毒进入受体，负调节 IFN 信号传导以调节宿主对 RSV 感染的抗病毒反应。
