Molecular mechanism of dysregulated airway antiviral responses in children with Trisomy 21

21三体综合征（TS 21）儿童住院和死亡的主要原因，也被称为唐氏症。 综合征（DS），是下呼吸道感染（LRTI）。患有DS的儿童的风险高出9倍， 呼吸道合胞病毒（RSV）引起的LRTI导致的住院和死亡。了解 需要驱动DS中严重病毒LRTI的高易感性的机制来开发新的治疗药物 治疗这种情况的策略。由于21号染色体（HSA 21）编码六种已知干扰素（IFN）中的四种， TS 21导致这些受体基因的三倍化，导致DS中的IFN超活化。与 IFN在抗病毒防御中的核心作用，IFN过度活化如何导致严重的病毒性肝炎仍然令人困惑。 DS中的LRTI。通过初步研究，我们发现，与整倍体对照相比， 来自DS儿童的AEC表现出IFN诱导的NRF 2调节异常，NRF 2是一种转录因子， 限制RSV复制所需的抗氧化反应。DS患儿的AEC也表现出失调， BACH 1及其抑制剂miR-155的表达，两者都位于HSA 21上，并调节NRF 2- 病毒感染期间依赖AEC的抗氧化反应。因此，我们的研究结果确定了一种新的机制， TS 21中气道抗病毒反应受损，并提供了两种广泛的 在DS中公认的细胞病理学-失调的IFN活化（干扰素病）和氧化失衡。 我们的中心假设是，干扰素在儿童气道上皮细胞的过度活化与DS BACH 1信号转导失调，导致抗病毒和NRF 2驱动的抗氧化反应降低 和更严重的病毒性呼吸道感染。我们的研究将解决DS的历史排除问题 儿童从气道抗病毒免疫相关的研究，因此将有变革的潜力， 改善他们的健康和生存。目的：探讨严重呼吸道感染的发病机制 感染的DS和开发创新的精准医疗方法，为这一脆弱的人群，我们 提出三个目标：目的1：确定IFN诱导的BACH 1失调在病毒呼吸道感染中的作用。 DS患儿气道上皮细胞感染。目的2：研究干扰素是如何改变 miR-155表达失调的儿童气道上皮抗氧化和抗病毒反应 DS.目的3：建立DS患者抗氧化和抗病毒反应失调与更大的 呼吸道病毒感染期间的疾病严重程度。这项以人为本的变革性研究的结果将 定义了一种以前未被认识到的导致抗氧化和抗病毒失调的靶向机制 在TS 21中回答。这一突破性的知识将大大推动我们对 DS中严重病毒性LRTI的病理生物学，并将为开发提供必要的分子基础 新的诊断工具和高度创新的疗法。

The leading cause of hospitalization and death in children with trisomy 21 (TS21), also known as Down syndrome (DS), is lower respiratory tract infection (LRTI). Children with DS have nine times higher risk of hospitalization and mortality due to LRTIs caused by respiratory syncytial virus (RSV). Understanding the mechanisms driving the high susceptibility to severe viral LRTI in DS is needed to develop novel therapeutic strategies to treat this condition. As chromosome 21(HSA21) encodes four of the six known Interferon (IFN) receptors, TS21 results in triplication of these receptor genes leading to IFN hyperactivation in DS. With the central role of IFNs on antiviral defense, it remains puzzling how IFN hyperactivation contributes to severe viral LRTIs in DS. Through preliminary studies we show that, compared to euploid controls, airway epithelial cells (AECs) from children with DS exhibit IFN-induced dysregulation of NRF2, a transcription factor essential for the antioxidant response required to limit RSV replication. The AECs of children with DS also show dysregulated expression of BACH1 and its inhibitor miR-155, both of which are located on HSA21, and regulate NRF2- dependent AEC antioxidant responses during viral infection. Thus, our results identify a novel mechanism of impaired airway antiviral responses in TS21, and provide an unexpected molecular nexus between two widely recognized cellular pathologies in DS - dysregulated IFN activation (interferonopathy) and oxidative imbalance. Our central hypothesis is that hyperactivation of IFN in the airway epithelium of children with DS dysregulates BACH1 signaling, leading to reduced antiviral and NRF2-driven antioxidant responses and greater severity of viral respiratory infection. Our study will address the historical exclusion of DS children from research related to airway antiviral immunity, and thus will have a transformative potential to improve their health and survival. To elucidate the mechanisms of pathogenesis of severe viral respiratory infections in DS and develop innovative precision medicine approaches for this vulnerable population, we propose three aims: AIM 1: Define the role of IFN-induced BACH1 dysregulation during viral respiratory infection in the airway epithelium of children with DS. AIM 2: Investigate how interferonopathy and altered miR-155 expression dysregulates antioxidative and antiviral responses in the airway epithelium of children with DS. AIM 3: Establish the association of dysregulated antioxidative and antiviral responses in DS with greater disease severity during respiratory viral infection. The result of this human-based transformative study will define a previously unrecognized targetable mechanism causing dysregulated anti-oxidative and antiviral responses in TS21. This ground-breaking knowledge will greatly move forward our understanding of the pathobiology of severe viral LRTI in DS and will provide the essential molecular foundation for the development of new diagnostic tools and highly innovative therapies.