Palani Sunil, Uddin Md Bashir, McKelvey Michael, Shao Shengjun, Wu Wenzhe, Bao Xiaoyong, Sun Jiaren, Sun Keer
The University of Texas Medical Branch at Galveston, Galveston, Texas, United States.
Sylhet Agricultural University, Sylhet, Sylhet Division, Bangladesh.
Am J Respir Cell Mol Biol. 2025 Jan 29. doi: 10.1165/rcmb.2024-0552OC.
Exposure to influenza A virus (IAV), respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) is well-known to increase the risk of pneumonia in humans. Type I interferon (IFN-I) is a hallmark response to acute viral infections, and alveolar macrophages (AMs) constitute the first line of airway defense against opportunistic bacteria. Our study reveals that virus-induced IFN-I receptor (IFNAR1) signaling directly impairs AM-dependent antibacterial protection. Using conditional knockout mouse models, in vivo antibodies, bone marrow chimeric mice, and AM reconstitution, we demonstrate that IFN-I intrinsically targets AMs to drive hypersusceptibility to following IAV infection. Importantly, we show that RSV and hMPV infection induces robust IFN-I signaling in AMs, coinciding with lethal susceptibility to secondary pneumonia. In contrast, seasonal human coronavirus neither induces significant IFN-I signaling in AMs nor immune predisposition to . Therefore, we conclude that IFN-I inhibition of AMs represents a crucial mechanism underlying antibacterial complications following otherwise asymptomatic or mild respiratory viral infections.
众所周知，感染甲型流感病毒（IAV）、呼吸道合胞病毒（RSV）和人偏肺病毒（hMPV）会增加人类患肺炎的风险。I型干扰素（IFN-I）是对急性病毒感染的标志性反应，而肺泡巨噬细胞（AM）构成了抵御机会性细菌的气道第一道防线。我们的研究表明，病毒诱导的I型干扰素受体（IFNAR1）信号直接损害AM依赖的抗菌保护作用。利用条件性敲除小鼠模型、体内抗体、骨髓嵌合小鼠和AM重建，我们证明IFN-I内在地靶向AM，导致IAV感染后对继发性肺炎的易感性增加。重要的是，我们发现RSV和hMPV感染在AM中诱导强烈的IFN-I信号，这与对继发性肺炎的致命易感性相一致。相比之下，季节性人类冠状病毒既不会在AM中诱导显著的IFN-I信号，也不会导致对继发性肺炎的免疫易感性。因此，我们得出结论，IFN-I对AM的抑制作用是无症状或轻度呼吸道病毒感染后抗菌并发症的关键机制。
