Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization
Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization
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DOI：
10.1172/jci125505
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发表时间：
2020-06-01
影响因子：
15.9
通讯作者：
Ato, Manabu
中科院分区：
文献类型：
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作者：
Shibata, Takehiko;Makino, Airi;Ato, Manabu
呼吸道合胞病毒（RSV）感染患者表现出对后续肺炎球菌感染的易感性增强。然而，这种易感性增加的潜在机制仍不清楚。在这里，我们确定了潜在的新的细胞和分子级联触发的RSV感染，加剧继发性肺炎球菌肺炎。RSV感染刺激局部产生生长抑制特异性6（Gas 6）。Gas 6受体Axl对于减弱肺炎球菌免疫至关重要，因为Gas 6/Axl阻断完全恢复了抗菌免疫。在机制上，Gas 6/Axl相互作用调节肺泡巨噬细胞从抗菌表型转化为不表现出抗菌活性的M2样表型，以及响应于肺炎球菌感染的半胱天冬酶-1活化和IL-18产生的衰减。减弱的IL-18产生不能驱动NK细胞介导的IFN-γ产生和局部NO和TNF-α产生，这损害了细菌感染的控制。因此，RSV介导的Gas 6/Axl活性减弱了巨噬细胞介导的针对肺炎球菌感染的保护。Gas 6/Axl轴可能是RSV相关继发性细菌感染的潜在新治疗靶点。
Patients with respiratory syncytial virus (RSV) infection exhibit enhanced susceptibility to subsequent pneumococcal infections. However, the underlying mechanisms involved in this increased susceptibility remain unclear. Here, we identified potentially novel cellular and molecular cascades triggered by RSV infection to exacerbate secondary pneumococcal pneumonia. RSV infection stimulated the local production of growth arrest-specific 6 (Gas6). The Gas6 receptor Axl was crucial for attenuating pneumococcal immunity in that the Gas6/Axl blockade fully restored antibacterial immunity. Mechanistically, Gas6/Axl interaction regulated the conversion of alveolar macrophages from an antibacterial phenotype to an M2-like phenotype that did not exhibit antibacterial activity, and the attenuation of caspase-1 activation and IL-18 production in response to pneumococcal infection. The attenuated IL-18 production failed to drive both NK cell-mediated IFN-gamma production and local NO and TNF-alpha production, which impair the control of bacterial infection. Hence, the RSV-mediated Gas6/Axl activity attenuates the macrophage-mediated protection against pneumococcal infection. The Gas6/Axl axis could be a potentially novel therapeutic target for RSV-associated secondary bacterial infection.