Influenza pathogenesis in pregnancy

妊娠期流感发病机制

基本信息

批准号：
10615124
负责人：
KRISTINA M. ADAMS WALDORF
金额：
$ 85.72万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-14 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615124
关键词：
Acute Animal Model Animals Antiviral Response Automobile Driving Autopsy Blood Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Cessation of life Clinical Coupled DNA Data Development Disease Disease susceptibility Fetus Flow Cytometry Frequencies Future Gene Expression Genes Genetic Transcription Gestational Age Heart Histopathology Host Defense Human IL17 gene Immune Immune response Impairment Infection Inflammasome Inflammatory Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Influenza A virus Injury Innate Immune Response Integration Host Factors Interferons Link Lung Lung Lavage Fluid Lung diseases Macaca nemestrina Maps Maternal Mortality Messenger RNA Modeling Morbidity - disease rate Myocarditis National Institute of Allergy and Infectious Disease Pathogenesis Pathogenicity Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Placenta Pneumonia Pregnancy Pregnant Women Premature Birth Quantitative Reverse Transcriptase PCR Resolution Risk Safety Sampling Site Stains Strategic Planning Structure of parenchyma of lung T cell response Testing Texas Time Tissues Vaccination Vaccines Villous Viral Viral Load result Virus Diseases Vulnerable Populations Whole Blood adaptive immune response adverse pregnancy outcome chemokine cytokine economic cost efficacy testing fetal gene network immune activation immunopathology influenzavirus innate immune pathways interleukin-23 lung injury maternal risk mouse model nonhuman primate organ injury pandemic preparedness pandemic virus pathogen phenotypic data pregnant prevent response safety testing single-cell RNA sequencing stillbirth transcription factor transcriptome transcriptome sequencing universal influenza vaccine vaccine platform white matter injury

项目摘要

Project Summary Pregnant women are highly vulnerable to influenza A virus (IAV) and are at increased risk for maternal death, preterm birth and stillbirth. Universal influenza vaccines (UFV) are thought to be possible if conserved regions of influenza virus are targeted and appropriate immune responses generated. However, relevant animal models are lacking in which to test such a vaccine, particularly for pregnant women. This proposal is focused on investigating maternal and placental immune responses to IAV in a pregnant nonhuman primate (NHP) model to understand the viral-host factors driving enhanced maternal disease. Our central hypothesis is that an aberrant Th17 response during an acute IAV infection leads to a broadly dysfunctional innate and adaptive immune response that prevents viral clearance and enhances risk for maternal death and stillbirth. Th17 cells produce high levels of the inflammatory cytokines IL-17 and IL-2218,19 with early Th17 polarization considered to be critical for IAV resolution; aberrant and/or late activation of the Th17 pathway by IL-23 in murine models is thought to impair viral clearance and promote lung injury.20,21 Our preliminary data in a pregnant NHP model of an acute IAV H1N1 infection demonstrates pneumonia in all animals by Day 5 post-IAV inoculation. In pregnant NHP, influenza disease scores were higher than non-pregnant animals with notable extra-pulmonary organ injury (myocarditis, white matter injury). Pregnant NHP demonstrated a nearly absent early Th17 CD4+ T cell response in whole blood and PBMC coupled with a marked increase in Th17 cells in the lung at peak immunopathology compared to non-pregnant animals. Inflammatory cytokines and chemokines in the lungs and bronchoalveolar lavage fluid (BAL) were also greater in pregnant versus non-pregnant animals. In Aim 1, non-pregnant and pregnant pigtail macaques will be challenged with either IAV H1N1 A/CA/04/09 or H3N2 A/Texas/71/2017 (N=8, each group) and undergo blood and BAL sampling until necropsy at Day 5 (peak immunopathology). In Aims 1A and 1B, we will determine pregnancy- specific immune correlates of IAV disease by evaluating the frequency of Th17 CD4+ T cells and a broad spectrum of innate/adaptive immune responses (i.e. immune cell subsets, cytokines/chemokines, Type I/III interferons) in the blood, BAL and lung. In Aim 1C, we will evaluate antiviral responses in the placenta linked to adverse pregnancy outcomes (e.g. cytokines/chemokines, NLRP3 inflammasome activation, CD8+ T cells). In Aim 2, we will use bulk and single cell RNA-sequencing to define changes in the transcriptome within PBMC, BAL, lung and placenta with a focus on Th17 transcriptional networks and antiviral innate immune pathways. In summary, the preliminary data indicates an aberrant Th17 response in pregnant animals, which is critical to promoting viral clearance and preventing lung injury. These studies will be the first to comprehensively analyze innate/adaptive immune responses during an acute IAV infection to elucidate the pathogenesis of severe lung disease in pregnant women. Results from these studies are critical for IAV pandemic preparedness to enable testing of efficacy and safety of new UFV.

项目概要孕妇极易感染甲型流感病毒 (IAV)，孕产妇死亡的风险也会增加，早产和死产。如果存在保守区域，通用流感疫苗（UFV）被认为是可能的。流感病毒被靶向并产生适当的免疫反应。然而，相关的动物模型是缺乏测试这种疫苗的方法，特别是针对孕妇。该提案的重点是调查在怀孕的非人灵长类动物 (NHP) 模型中对 IAV 的母体和胎盘免疫反应，以了解病毒宿主因素导致孕产妇疾病加剧。我们的中心假设是异常的 Th17 反应在急性 IAV 感染期间，会导致先天性和适应性免疫反应广泛功能失调，阻止病毒清除并增加孕产妇死亡和死产的风险。 Th17 细胞产生高水平炎症细胞因子 IL-17 和 IL-2218,19 以及早期 Th17 极化被认为对 IAV 至关重要解决;在小鼠模型中，IL-23 对 Th17 通路的异常和/或晚期激活被认为会损害病毒清除并促进肺损伤。20,21 我们在急性 IAV H1N1 感染的妊娠 NHP 模型中的初步数据在 IAV 接种后第 5 天，所有动物均出现肺炎。在怀孕的 NHP 中，流感疾病评分高于有明显肺外器官损伤（心肌炎、白质损伤）的非妊娠动物。怀孕的 NHP 在全血和 PBMC 耦合中表现出几乎不存在的早期 Th17 CD4+ T 细胞反应与非怀孕动物相比，在免疫病理学高峰期，肺部的 Th17 细胞显着增加。肺部和支气管肺泡灌洗液 (BAL) 中的炎症细胞因子和趋化因子在怀孕动物与非怀孕动物。在目标 1 中，将挑战未怀孕和怀孕的猪尾猕猴感染 IAV H1N1 A/CA/04/09 或 H3N2 A/Texas/71/2017（每组 N=8）并接受血液和 BAL 采样直至第 5 天尸检（免疫病理学峰值）。在目标 1A 和 1B 中，我们将确定怀孕- 通过评估 Th17 CD4+ T 细胞的频率和广谱来确定 IAV 疾病的特异性免疫相关性先天/适应性免疫反应（即免疫细胞亚群、细胞因子/趋化因子、I/III 型干扰素）血液、BAL 和肺。在目标 1C 中，我们将评估与不良妊娠相关的胎盘抗病毒反应结果（例如细胞因子/趋化因子、NLRP3 炎性体激活、CD8+ T 细胞）。在目标 2 中，我们将使用批量和单细胞 RNA 测序，以定义 PBMC、BAL、肺和胎盘内转录组的变化重点关注 Th17 转录网络和抗病毒先天免疫途径。综上，初步数据表明怀孕动物中存在异常的 Th17 反应，这对于促进病毒清除和预防肺损伤。这些研究将是第一个全面分析先天/适应性免疫反应的研究在急性 IAV 感染期间，以阐明孕妇严重肺部疾病的发病机制。结果来自这些研究对于 IAV 大流行的防范至关重要，可以测试新型 UFV 的功效和安全性。