Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.
Department of Biomolecular Science, Faculty of Science, Toho University, Chiba, Japan.
J Clin Invest. 2020 Jun 1;130(6):3021-3037. doi: 10.1172/JCI125505.
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-γ production and local NO and TNF-α 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.
呼吸道合胞病毒 (RSV) 感染的患者对随后的肺炎球菌感染表现出增强的易感性。然而，这种易感性增加所涉及的潜在机制尚不清楚。在这里，我们确定了 RSV 感染引发的潜在新的细胞和分子级联反应，以加重继发性肺炎球菌肺炎。RSV 感染刺激生长停滞特异性 6（Gas6）的局部产生。Gas6 受体 Axl 对于减弱肺炎球菌免疫至关重要，因为 Gas6/Axl 阻断完全恢复了抗菌免疫。在机制上，Gas6/Axl 相互作用调节肺泡巨噬细胞从具有抗菌表型向不具有抗菌活性的 M2 样表型的转化，并且减弱了对肺炎球菌感染的半胱天冬酶-1 激活和 IL-18 产生的反应。减弱的 IL-18 产生未能驱动 NK 细胞介导的 IFN-γ 产生和局部 NO 和 TNF-α 产生，从而损害对细菌感染的控制。因此，RSV 介导的 Gas6/Axl 活性减弱了巨噬细胞介导的对肺炎球菌感染的保护作用。Gas6/Axl 轴可能是 RSV 相关继发性细菌感染的一个潜在新的治疗靶点。
