Understanding the Impact of Influenza A Virus Infection During Pregnancy

了解甲型流感病毒感染对怀孕期间的影响

基本信息

项目摘要

PROJECT SUMMARY A successful pregnancy is associated with an intricate immunological balance that is crucial in supporting the presence and development of a "foreign" fetus. This balance is marked by physiological changes that can alter the lung compartment, including the need for increased oxygen consumption, which can influence pregnant women's response to respiratory infections. For example, influenza A virus (IAV) infection during pregnancy is more likely to result in severe disease, including hospitalization and even death. During the 2009 pandemic, 29% of influenza-associated hospital admissions and up to 16% of deaths were in pregnant women. Maternal IAV infection can also negatively impact the offspring, including increases in spontaneous abortions, fetal death, small gestational age (SGA), and cognitive dysfunction. Despite these detrimental outcomes, insight into the underlying mechanisms is still sparse. A fundamental gap in our knowledge is understanding how remodeling of the lung microenvironment during distinct gestational stages affects the response to IAV infection. A significant barrier to further these studies has been the difficulty to reliably define gestational dates. To fill this gap in knowledge, I have employed a robust and reproducible pregnant mouse model whereby I use ultrasound analysis to more accurately determine the gestational date allowing me to infect pregnant dams at early gestation (embryonic day (E)8.5), mid-gestation (E10.5) and at the commonly used E12.5 timepoint, which represents late gestation. My in vivo studies have shown that maternal IAV infection during early gestation is associated with increased mortality due to lung damage compared to non-pregnant infected mice and mice infected later in pregnancy, highlighting stage-dependent susceptibility and disease. In pregnant mice infected early in gestation, I found that there is increased septal thickening and denuded bronchioles suggesting damage to the lung’s stroma. In collaboration with Dr. Paul Thomas's laboratory, our group recently demonstrated the critical role for stromal cells in regulating and remodeling the lung microenvironment during response and repair to influenza (Boyd et al., Nature 2020). Collectively, this leads me to hypothesize that the gestational stage modulates IAV pathogenesis by altering the lung microenvironment, including marked changes in the lung's stromal cell populations. I will utilize integrative approaches including histology, flow-cytometry-based assays, single-cell gene-expression profiling (scEX), and bioinformatics. To address this hypothesis, in Aim 1, I will further assess, quantify and functionally determine how gestational stage can mediate increased IAV pathogenesis in the pregnant mother. Aim 2 will further define the impact of gestational influenza infection on maternal lung stromal cells, a severely understudied area. Upon completion, these studies will have major implications on the critical gestational window that could be targeted to maximize protection for the mother and fetus from IAV infection, including restructuring vaccine regimens and therapeutic interventions.
项目摘要 成功的怀孕与复杂的免疫平衡有关,这对支持怀孕至关重要。 “外来”胎儿的存在和发育。这种平衡以生理变化为标志, 肺室,包括需要增加氧气消耗,这可能会影响怀孕 女性对呼吸道感染的反应。例如,怀孕期间感染甲型流感病毒(IAV), 更有可能导致严重的疾病,包括住院甚至死亡。在2009年大流行期间,29% 与流感相关的住院病例和高达16%的死亡病例为孕妇。母体IAV 感染也会对后代产生负面影响,包括自然流产,胎儿死亡, 小胎龄(SGA)和认知功能障碍。尽管有这些不利的结果,深入了解 潜在的机制仍然稀少。我们知识中的一个根本空白是理解 不同妊娠期的肺微环境影响对IAV感染的反应。显著 进一步研究的障碍是难以可靠地确定妊娠日期。为了填补这一空白, 知识,我已经采用了一个强大的和可重复的怀孕小鼠模型,我使用超声 分析,以更准确地确定妊娠日期,使我能够在妊娠早期感染妊娠母鼠 (胚胎日(E)8.5)、妊娠中期(E10.5)和通常使用的E12.5时间点,其代表晚期 怀孕我的体内研究表明,妊娠早期母体感染IAV与以下因素有关: 与未怀孕的感染小鼠和在怀孕后感染的小鼠相比, 妊娠,强调阶段依赖性易感性和疾病。在妊娠早期感染的怀孕小鼠中, 我发现肺间隔增厚和细支气管裸露表明肺损伤 基质。在与保罗托马斯博士的实验室合作中,我们的团队最近证明了 基质细胞在流感应答和修复过程中调节和重塑肺微环境 (Boyd例如,Nature 2020)。总的来说,这使我假设妊娠期调节IAV 通过改变肺微环境,包括肺基质细胞的显著变化, 人口。我将利用综合方法,包括组织学,流式细胞术为基础的测定,单细胞 基因表达谱(scEX)和生物信息学。为了解决这个假设,在目标1中,我将进一步评估, 定量和功能性地确定妊娠期如何介导IAV发病机制的增加, 怀孕的母亲目的2将进一步明确妊娠期流感感染对母体肺间质的影响, 细胞,一个严重研究不足的领域。这些研究完成后,将对关键的 妊娠窗口期,可以有针对性地最大限度地保护母亲和胎儿免受IAV感染, 包括调整疫苗方案和治疗干预措施。

项目成果

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Ana Vazquez-Pagan其他文献

Ana Vazquez-Pagan的其他文献

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{{ truncateString('Ana Vazquez-Pagan', 18)}}的其他基金

Understanding the Impact of Influenza A Virus Infection During Pregnancy
了解甲型流感病毒感染对怀孕期间的影响
  • 批准号:
    10390105
  • 财政年份:
    2022
  • 资助金额:
    $ 2万
  • 项目类别:

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