Boehme Julia D, Jeron Andreas, Schultz Kristin, Melcher Lars, Schott Katharina, Gelmez Elif, Kröger Andrea, Stegemann-Koniszewski Sabine, Bruder Dunja
Infection Immunology Group, Institute of Medical Microbiology and Hospital Hygiene, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke University, Magdeburg, Germany.
Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Cell Commun Signal. 2025 Jun 12;23(1):278. doi: 10.1186/s12964-025-02284-y.
Pneumococcal pneumonia following influenza A virus (IAV) infection is a synergistic complication with high mortality in which IAV infection modulates host antibacterial responses and affects bacterial invasiveness of Streptococcus pneumoniae (S. pn.). IAV-mediated effects can last beyond viral clearance. In acute IAV pneumonia, alveolar type II epithelial cells (AECII) are primary targets for viral replication and contribute to the immune response. Our study addresses sustained effects of IAV infection on AECII and consequences for their response towards different serotypes of S. pn.
We analyzed bacterial loads, respiratory inflammation and AECII gene transcription profiling in mice infected with IAV and/or one of three S. pn. serotypes of varying invasiveness (4 > 7F > 19F). We inferred a scale-free-like ARACNE gene co-expression network on AECII transcriptional regulation under these conditions. We performed Western blotting for protein expression of interferon signaling components in AECII. We additionally performed ATAC-seq analysis of AECII isolated 14 days following IAV infection.
Previous IAV infection rendered the lung susceptible to invasive S. pn. infection with serotype 4 and the mildly invasive 7F but not 19F. Particularly secondary infection with 7F induced exacerbated inflammatory responses as compared to bacterial infection alone, marked by increased protein expression of type I and II interferons. AECII gene co-expression network revealed interferon-response network modules. Network-mapping unfolded S. pn. serotype-specific transcriptional network responses/usage and secondary S. pn. infection was found to abrogate an IAV-induced AECII proliferative configuration. Enhanced expression of several ARACNE network genes were found to be associated with increased chromatin accessibility at their promoter regions.
Our study demonstrates AECII to retain a sustained IAV-associated configuration with epigenetic involvement, affecting their proliferation and serotype-specifically intensifying their transcriptional response, mainly to interferons, in secondary S. pn.
In a broader context, our results suggest the concepts of peripheral inflammatory imprinting and trained innate immunity to apply to cells of the respiratory epithelium in the context of subsequent viral/bacterial challenges.
甲型流感病毒（IAV）感染后的肺炎链球菌肺炎是一种协同并发症，死亡率很高，其中IAV感染会调节宿主的抗菌反应，并影响肺炎链球菌（S. pn.）的细菌侵袭性。IAV介导的影响可持续到病毒清除之后。在急性IAV肺炎中，II型肺泡上皮细胞（AECII）是病毒复制的主要靶细胞，并参与免疫反应。我们的研究探讨了IAV感染对AECII的持续影响以及其对不同血清型肺炎链球菌反应的后果。
我们分析了感染IAV和/或三种侵袭性不同的肺炎链球菌血清型之一（4＞7F＞19F）的小鼠的细菌载量、呼吸道炎症和AECII基因转录谱。我们在这些条件下推断了一个类似无标度的ARACNE基因共表达网络用于AECII的转录调控。我们对AECII中干扰素信号成分的蛋白表达进行了蛋白质印迹分析。我们还对IAV感染14天后分离的AECII进行了ATAC-seq分析。
先前的IAV感染使肺部易受血清型4和轻度侵袭性的7F肺炎链球菌的侵袭性感染，但对19F血清型不敏感。与单独的细菌感染相比，特别是7F血清型的继发感染诱导了更强烈的炎症反应，其特征是I型和II型干扰素的蛋白表达增加。AECII基因共表达网络揭示了干扰素反应网络模块。网络映射揭示了肺炎链球菌血清型特异性转录网络反应/用途，并且发现继发的肺炎链球菌感染消除了IAV诱导的AECII增殖构型。发现几个ARACNE网络基因的表达增强与它们启动子区域染色质可及性增加有关。
我们的研究表明AECII保留了与IAV相关的持续构型，并涉及表观遗传学，影响其增殖，并血清型特异性地增强其转录反应，主要是对继发肺炎链球菌感染中的干扰素的反应。
在更广泛的背景下，我们的结果表明外周炎症印记和训练有素的先天免疫的概念适用于后续病毒/细菌挑战背景下的呼吸道上皮细胞。
