免疫学
肺炎球菌肺炎
支气管肺泡灌洗
肺炎
甲型流感病毒
肺炎链球菌
先天免疫系统
医学
肺
病毒
免疫系统
肿瘤坏死因子α
细菌性肺炎
人口
生物
微生物学
内科学
抗生素
环境卫生
作者
Christina Malainou,Christin Peteranderl,Maximiliano Ruben Ferrero,Ana Ivonne Vazquez‐Armendariz,Ioannis Alexopoulos,Julian Better,Mohammad Estiri,Hendrik Schultheis,Judith Hoppe,María‐Luisa del Rio,José-Ignacio Rodríguez-Barbosa,Klaus Pfeffer,Stefan Günther,Mario Looso,Achim D. Gruber,István Vadász,Ulrich Matt,Susanne Herold
标识
DOI:10.1101/2024.07.28.605445
摘要
Abstract Secondary bacterial infection, often caused by Streptococcus pneumoniae (Spn), is one of the most frequent and severe complications of influenza A virus (IAV)-induced pneumonia. Phenotyping of the pulmonary innate immune landscape after IAV infection revealed a significant depletion of the tissue-resident alveolar macrophage (TR-AM) population at day 7, which was associated with increased susceptibility to Spn outgrowth. To elucidate the molecular mechanisms underlying TR-AM depletion, and to define putative targets for treatment, we combined single-cell transcriptomics and cell-specific PCR profiling in an unbiased manner, using in vivo models of IAV infection and IAV/Spn co-infection. The TNF superfamily 14 (TNFSF14) ligand-receptor axis was revealed as the driving force behind post-influenza TR-AM death during the early infection phase, enabling the transition to pneumococcal pneumonia, while intrapulmonary transfer of genetically modified TR-AMs and antibody-mediated neutralization of specific pathway components alleviated disease severity. With a mainly neutrophilic expression and a high abundance in the bronchoalveolar fluid (BALF) of patients with severe virus-induced ARDS, TNFSF14 emerged as a novel determinant of virus-driven lung injury. Targeting the TNFSF14-mediated intercellular communication network in the virus-infected lung can, therefore, improve host defense, minimizing the risk of subsequent bacterial pneumonia, and ameliorating disease outcome.
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