Respiratory Syncytial Virus (RSV) is the major cause of lower respiratory tract infection in infants, in whom, the sensing of RSV by innate immune receptors and its regulation are still poorly described. However, the severe bronchiolitis following RSV infection in neonates has been associated with a defect in type I interferons (IFN-I) production, a cytokine produced mainly by alveolar macrophages (AMs) upon RSV infection in adults. In the present study, neonatal C57BL/6 AMs mobilized very weakly the IFN-I pathway upon RSV infection in vitro and failed to restrain virus replication. However, IFN-I productions by neonatal AMs were substantially increased by the deletion of Insulin-Responsive AminoPeptidase (IRAP), a protein previously involved in the regulation of IFN-I production by dendritic cells. Moreover, neonatal IRAP^KO AMs showed a higher expression of IFN-stimulated genes than their wild-type C57BL/6 counterpart. Interestingly, depletion of IRAP did not affect adult AM responses. Finally, we demonstrated that newborn IRAP^KO mice infected with RSV had more IFN-I in their lungs and eliminated the virus more efficiently than WT neonates. Taken together, early-life susceptibility to RSV infection may be related to an original age-dependent suppressive function of IRAP on the IFN-I driven-antiviral responses in neonatal AMs.

呼吸道合胞病毒 (RSV) 是婴儿下呼吸道感染的主要原因，在婴儿中，先天免疫受体对 RSV 的感知及其调控仍知之甚少。然而，新生儿 RSV 感染后的严重毛细支气管炎与 I 型干扰素 (IFN-I) 产生缺陷有关，IFN-I 是成人 RSV 感染时主要由肺泡巨噬细胞 (AMs) 产生的一种细胞因子。在本研究中，新生儿 C57BL/6 AM 在体外 RSV 感染后动员 IFN-I 通路的能力非常弱，并且未能抑制病毒复制。然而，新生儿 AM 产生的 IFN-I 因胰岛素反应性氨基肽酶 (IRAP) 的缺失而显着增加，IRAP 是一种先前参与调节树突细胞 IFN-I 产生的蛋白质。此外，新生儿 IRAP^KO AMs 显示出比其野生型 C57BL/6 对应物更高的 IFN 刺激基因表达。有趣的是，IRAP 的消耗不会影响成人 AM 反应。最后，我们证明感染 RSV 的新生 IRAP ^{KO小鼠肺部有更多的 IFN-I，并且比 WT 新生儿更有效地消除病毒。}总之，生命早期对 RSV 感染的易感性可能与 IRAP 对新生儿 AM 中 IFN-I 驱动的抗病毒反应的原始年龄依赖性抑制功能有关。