Analysis of influenza-mediated alterations in alveolar type II epithelial cell (AECII) responsiveness as a mechanism underlying enhanced susceptibility to secondary pneumococcal infection

分析流感介导的肺泡 II 型上皮细胞 (AECII) 反应性变化作为继发性肺炎球菌感染易感性增强的机制

• 批准号: 326600522
• 负责人: Professorin Dr. Dunja Bruder
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Krankenhaushygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/326600522?language=en
• 关键词: Analysis; influenza; mediated; alterations; alveolar

Type II alveolar epithelial cells (AECII) are resident cells of the lower respiratory tract with an increasingly recognized immunological potential. They are targeted by the influenza A virus (IAV) for replication and rapidly react to viral infection with the production of cytokines and chemokines. However, not only viral infections trigger AECII responses, but they also respond to bacterial ligands and have been shown to essentially contribute to anti-bacterial defense. Epidemiological data from historic as well as recent influenza pandemics clearly documents strongly enhanced susceptibility to secondary bacterial infection following influenza, especially with S. pneumoniae. While this synergism was originally explained by epithelial destruction through the viral infection, we know today that IAV has a long-term modulating effect on host respiratory immunity. The proposed project aims at uncovering IAV-mediated changes in the responsiveness of AECII towards bacterial triggers as an underlying mechanism. AECII have so far been neglected as possible players in the viral/bacterial synergism, despite their role in anti-bacterial defense - which is however insufficiently characterized to date. Therefore we will first characterize the AECII anti-pneumococcal response in detail to subsequently assess IAV-mediated alterations present after recovery from the viral infection. This will take place on the one hand on a global gene transcriptional level through microarray analyses of primary AECII isolated from infected mice. On the other hand we aim at increasing our understanding of the direct interaction of AECII with the bacterium by analyzing bacterial penetration of AECII and induction of apoptosis both in situ and ex vivo with primary cells from naïve as well as previously IAV infected hosts. Importantly, here we will also take into account bacterial factors influencing the AECII/pneumococcal interaction by including different strains of selected S. pneumoniae serotypes. Taken together, these analyses will shed light on how a resolved IAV infection imprints the respiratory epithelium, affecting its responsiveness to pneumococcal encounters and thereby enhancing susceptibility to secondary bacterial infections. By taking AECII into account as new players in respiratory immune modulation following influenza, we are aiming towards a complete understanding of the processes underlying the synergism between IAV and S. pneumoniae - an understanding which will be the crucial basis for the development of strategies for treatment and prophylaxis in the future.

II型肺泡上皮细胞（AECII）是下呼吸道的常驻细胞，具有越来越多的免疫潜力。它们被甲型流感病毒（IAV）靶向复制，并通过产生细胞因子和趋化因子对病毒感染迅速作出反应。然而，不仅病毒感染触发AECII反应，而且它们也对细菌配体产生反应，并且已显示出基本上有助于抗菌防御。历史上以及最近的流感大流行的流行病学数据清楚地表明，流感后继发性细菌感染的易感性强烈增强，特别是S。肺炎。虽然这种协同作用最初被解释为通过病毒感染破坏上皮细胞，但我们今天知道IAV对宿主呼吸免疫具有长期调节作用。拟议的项目旨在揭示IAV介导的AECII对细菌触发物的反应性变化作为一种潜在机制。AECII作为病毒/细菌协同作用的可能参与者迄今为止一直被忽视，尽管它们在抗细菌防御中的作用-然而迄今为止其特征还不充分。因此，我们将首先详细描述AECII抗肺炎球菌反应，随后评估IAV介导的病毒感染恢复后的变化。这将发生在一方面，在全球基因转录水平上，通过微阵列分析的主要AECII从感染的小鼠分离。另一方面，我们的目的是增加我们的AECII与细菌的直接相互作用的理解，通过分析AECII的细菌渗透和诱导细胞凋亡原位和离体与原代细胞从天真的，以及以前的IAV感染的主机。重要的是，在这里我们还将考虑影响AECII/肺炎球菌相互作用的细菌因素，包括选择的S.肺炎血清型。综上所述，这些分析将揭示如何解决IAV感染印记呼吸道上皮，影响其对肺炎球菌的反应，从而提高继发性细菌感染的易感性。通过考虑AECII作为流感后呼吸道免疫调节的新参与者，我们的目标是全面了解IAV和S之间协同作用的过程。肺炎-这将是在未来的治疗和预防策略的发展的关键基础的理解。