Mechanisms of age-specific differences in the Type I IFN response to respiratory viral infection

I型干扰素对呼吸道病毒感染反应的年龄特异性差异机制

• 批准号: 10256608
• 负责人: Alison J Carey
• 金额: $ 45.06万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256608
• 关键词: 37 weeks gestation; Adult; Affect; Age; Age-Months; Animal Model; Antioxidants; Antiviral Agents; Autopsy; Birth; C57BL/6 Mouse; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Coculture Techniques; Cysteine; Data; Development; Epithelial Cells; Equilibrium; Evolution; Flow Cytometry; Gene Expression Profile; Genes; Genetic Transcription; Hour; Human; Immune; Immune response; Immune system; Infant; Infection; Inflammation; Inflammatory; Influenza; Interferon Receptor; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; Kinetics; Knowledge; Life; Literature; Lung; Measures; Modeling; Molecular; Mus; Neonatal; Neonatal Mortality; Newborn Animals; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Placebos; Population; Pregnancy; Preventive treatment; Production; RNA; Research; Respiratory System; Role; Secondary to; Structure of parenchyma of lung; Survival Rate; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Viral Load result; Viral Respiratory Tract Infection; Virus Diseases; Vulnerable Populations; Work; age group; base; biological adaptation to stress; cell type; cytokine; histopathological examination; improved; in vivo; in vivo Model; infant death; influenza infection; influenza virus vaccine; influenzavirus; innovation; insight; mature animal; mortality; mouse model; nano-string; neonatal infection; neonatal mice; neonate; next generation sequencing; pathogen; preterm newborn; receptor; respiratory virus; response; transcriptome

Project Summary/Abstract Respiratory viral infections contribute substantially to global infant losses and disproportionately affect preterm neonates. Of all deaths less than 12 months of age secondary to a respiratory viral infection, 55% occur in a neonate born before 30 weeks gestation. Until recently, most research about neonatal and infant primary immune response to viral infections was based on data from adult animal models generalized to the neonate. Current data suggest that a more relevant model for the human infant is the neonatal mouse because of a similar evolution of the immune system post-birth. We have established a 3-day old murine model of infant influenza virus infection, comparable to a late preterm (34-37 weeks gestation) human neonate. To determine age-specific differences in the initial innate response to influenza virus, we measured by Nanostring technology RNA transcriptional changes in 753 immune-related genes induced in neonatal and adult whole lungs 12 hours after PR8 influenza virus infection and uninfected age-matched neonates. Twelve hours after infection, the neonatal mouse had a similar transcriptional profile to an uninfected age-matched mouse, whereas the infected adult mouse upregulated hundreds of genes, especially in the type I interferon (IFN) pathway, an essential component of antiviral defense. Although type I IFNs induce key antiviral pathways, IFNs can also serve to amplify proinflammatory responses, which can increase damage in the respiratory tract in adults. However, the infant-specific type I IFN kinetic and whether type I IFNs are protective or deleterious to infants represents a significant knowledge gap. In preliminary studies, neonatal mice devoid of the type I IFN receptor (IFNαβR-/-) had a greatly improved survival rate of 80% after influenza virus infection, compared to the C57BL/6 survival rate of only 15%. This is in direct opposition to adult mice, where viral infection is more pathogenic in the absence of a type I IFN response. We hypothesize that the neonate has an aberrant type I IFN kinetic in response to influenza virus which directly leads to oxidative stress, inflammation and lung tissue damage. Since the presence of IFNαβ receptor is protective in adults, we also hypothesize that differences in neonatal IFNαβ receptor-dependent responses may involve distinct downstream pathways than the adult type I IFN response. To test this hypothesis, we propose to investigate developmental differences in the infant response to respiratory viral infection through a powerful combination of next generation sequencing, an in vivo neonatal mouse infection model and an innovative primary neonatal lung epithelial cell culture. Key in vivo transcriptome differences will be determined in neonatal and adult, naïve and influenza-infected, C57BL/6 and IFNαβR-/- FACS purified murine lung Type II epithelial cells. We will also define age-specific type I IFN kinetic differences which promote an oxidative stress response in neonatal influenza-infected lung epithelial cells which contributes to pathogenicity. Finally, we will test if an anti-oxidant (N-acetyl cysteine) is a reasonable therapeutic option to treat infant respiratory viral infection in this extremely vulnerable population.

项目摘要/摘要 呼吸道病毒感染对全球婴儿的损失产生了重大贡献，并且不成比例地影响早产 新生儿。在呼吸道病毒感染继发的所有小于12个月大的死亡中，有55％发生在A 妊娠30周之前出生的新生儿。直到最近，关于新生儿和婴儿主要的大多数研究 对病毒感染的免疫反应是基于从成年动物模型中推广到新生儿的数据。 当前数据表明，人类婴儿的更相关模型是新生小鼠，因为 出生后免疫系统的类似演变。我们已经建立了一个为期三天的婴儿的鼠模型 流感病毒感染，与早产晚期（妊娠34-37周）相当。确定 最初对影响病毒的天生反应的年龄特异性差异，我们通过纳米串技术衡量 在新生儿和成年肺中诱导的753个免疫相关基因的RNA转录变化12小时 PR8影响病毒感染和未感染年龄匹配的新生儿。感染十二个小时后， 新生小鼠具有与未感染年龄匹配的鼠标相似的转录曲线，而 感染的成年小鼠更新了数百个基因，尤其是在I型干扰素（IFN）途径中 抗病毒防御的重要组成部分。尽管I型IFN诱导关键抗病毒途径，但IFN也可以 用于扩大促炎反应，这可能会增加成人呼吸道的损害。 但是，婴儿特定的I型IFN动力学以及I型IFN是否受到婴儿的保护或有害 代表一个重要的知识差距。在初步研究中，没有I型IFN受体的新生小鼠 （IFNαβR - / - ）与影响力相比，影响力病毒感染后的生存率大大提高了80％ C57BL/6的存活率仅为15％。这是直接与成年小鼠相反的，那里的病毒感染更多 在没有I型IFN响应的情况下，致病性。我们假设新生儿具有异常的I类 IFN动力学响应影响病毒，直接导致氧化应激，感染和肺组织 损害。由于IFNαβ受体的存在受到成人的保护，我们还假设 新生儿IFNαβ受体依赖性反应可能涉及与成人I型不同的下游途径 IFN响应。为了检验这一假设，我们建议研究婴儿的发育差异 下一代测序的强大组合对呼吸道病毒感染的反应，体内 新生小鼠感染模型和创新的原发性新生儿肺上皮细胞培养。键入体内 转录组差异将在新生儿和成人，幼稚和影响力感染的情况下确定，C57BL/6和 IFNαβR - / - FACS纯化的鼠肺II型上皮细胞。我们还将定义特定年龄的I型IFN动力学 促进新生儿影响核上皮细胞中氧化应激反应的差异 这有助于致病性。最后，我们将测试抗氧化剂（N-乙酰基半胱氨酸）是否合理 在这种极脆弱的人群中治疗婴儿呼吸道病毒感染的治疗选择。