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

批准号：
10390105
负责人：
Ana Vazquez-Pagan
金额：
$ 4.28万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390105
关键词：
Address Affect Area Bioinformatics Biological Assay Bronchioles CD8-Positive T-Lymphocytes Cells Cessation of life Collaborations Data Data Analyses Development Disease Embryo Equilibrium Extracellular Matrix Proteins Fetal Death Fetus Fibroblasts Flow Cytometry Gene Expression Profiling Gene set enrichment analysis Genetic Transcription Gestational Age Hematoxylin and Eosin Staining Method Heterogeneity Histology Hospitalization Immune Immune response Immunologics Impaired cognition Infection Inflammation Influenza Influenza A virus Knowledge Laboratories Literature Lung Lymphocyte Mediating Methods Mothers Mus Nature Outcome Oxygen Oxygen Consumption PTPRC gene Physiological Play Population Predisposition Pregnancy Pregnant Women Regimen Reproducibility Respiratory Tract Infections Role Scientist Severity of illness Small for Gestational Age Infant Spontaneous abortion Stains Stromal Cells Structure of parenchyma of lung Therapeutic Intervention Tissues Training Tumor-infiltrating immune cells Vaccines Viral Pathogenesis Viral Respiratory Tract Infection Virus Diseases base experience experimental study fetal immunopathology in vivo influenza infection insight lung injury lung repair meetings mortality mouse model offspring pandemic disease pathogenic virus pregnant recruit repaired response skills ultrasound

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，这对于支持 “外国”胎儿的存在和发展。这种平衡的标志是可以改变的身体变化肺部室，包括增加氧气消耗的需求，这可能会影响怀孕妇女对呼吸道感染的反应。例如，怀孕期间的影响病毒（IAV）感染是更可能导致严重疾病，包括住院甚至死亡。在2009年大流行期间，有29％孕妇与影响力相关的医院入院和多达16％的死亡。母亲IAV 感染还会对后代产生负面影响，包括自发流产，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，但对潜在机制仍然很少。我们知识上的根本差距是了解如何重塑在不同的妊娠阶段，肺微环境影响对IAV感染的反应。重要的进一步的这些研究的障碍很难可靠地定义妊娠日期。填补这个空白知识，我工作了一个强大且可再现的孕妇模型，我可以使用超声波分析以更准确地确定妊娠日期，使我能够在妊娠早期感染怀孕的大坝（胚胎日（E）8.5），中期（E10.5）和常用的E12.5时点，代表迟到妊娠。我的体内研究表明，早期妊娠期间的感染与与未怀孕感染的小鼠相比，由于肺部损害而增加的死亡率增加，后来感染了小鼠怀孕，突出了阶段依赖性的敏感性和疾病。在妊娠早期感染的怀孕小鼠中，我发现中间增厚和裸支气管的增加，暗示对肺部的损害基质。与保罗·托马斯（Paul Thomas）的实验室合作，我们的小组最近展示了在反应和修复过程中调节和重塑肺微环境中的基质细胞以影响（Boyd等人，自然2020）。总的来说，这使我假设妊娠期调节了IAV 通过改变肺微环境，发病机理，包括肺部基质细胞的明显变化人群。我将利用整合方法，包括组织学，基于流程仪的测定，单细胞基因表达分析（SCEX）和生物信息学。为了解决这一假设，在AIM 1中，我将进一步评估，量化并在功能上确定妊娠阶段如何介导IAV发病机理的增加怀孕的母亲。 AIM 2将进一步定义妊娠影响对Mater Lung Stromal的影响细胞，一个非常了解的区域。完成后，这些研究将对关键产生重大影响妊娠窗口可以针对最大化母亲和胎儿免受IAV感染的保护，包括重组疫苗方案和治疗干预措施。