Influenza pathogenesis in pregnancy
妊娠期流感发病机制
基本信息
- 批准号:10312331
- 负责人:
- 金额:$ 86.4万
- 依托单位:
- 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:
- 关键词:AcuteAnimal ModelAnimalsAntiviral AgentsAntiviral ResponseAutomobile DrivingAutopsyBloodBronchoalveolar LavageBronchoalveolar Lavage FluidCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCellsCessation of lifeChorionClinicalCoupledDataDevelopmentDiseaseDisease susceptibilityFetusFlow CytometryFrequenciesFutureGene ExpressionGenesGenetic TranscriptionGestational AgeHeartHistopathologyHost DefenseHumanImmuneImmune responseImpairmentInfectionInflammasomeInflammatoryInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza A Virus, H3N2 SubtypeInfluenza A virusInjuryIntegration Host FactorsInterferonsInterleukin-17LinkLungLung diseasesMacaca nemestrinaMapsMaternal MortalityModelingMorbidity - disease rateMyocarditisNational Institute of Allergy and Infectious DiseasePathogenesisPathogenicityPathway interactionsPatientsPeripheral Blood Mononuclear CellPhenotypePlacentaPneumoniaPregnancyPregnant WomenPremature BirthQuantitative Reverse Transcriptase PCRResolutionRiskSafetySamplingSiteStainsStrategic PlanningStructure of parenchyma of lungT cell responseTestingTexasTimeTissuesVaccinationVaccinesVillousViralViral Load resultVirus DiseasesVulnerable PopulationsWhole Bloodadaptive immune responseadverse pregnancy outcomechemokinecostcytokineearly pregnancyefficacy testingfetalimmune activationimmunopathologyinfluenzavirusinnate immune pathwaysinterleukin-23lung injurymaternal riskmouse modelnonhuman primateorgan injurypandemic diseasepandemic preparednessphenotypic datapregnantpreventresponsesafety testingsingle-cell RNA sequencingstillbirthtranscription factortranscriptometranscriptome sequencinguniversal influenza vaccinewhite 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.
项目摘要
孕妇非常容易感染甲型流感病毒(IAV),并且孕产妇死亡的风险增加,
早产和死胎。通用流感疫苗(UFV)被认为是可能的,如果保守的区域,
靶向流感病毒并产生适当免疫应答。然而,相关的动物模型是
缺乏测试这种疫苗的方法,特别是对孕妇。这项建议的重点是调查
妊娠非人灵长类动物(NHP)模型中母体和胎盘对IAV的免疫应答,以了解
病毒宿主因素导致母体疾病加重。我们的中心假设是,异常的Th17应答
在急性IAV感染期间,导致先天性和适应性免疫应答功能广泛失调,
阻止病毒清除并增加孕产妇死亡和死产的风险。Th17细胞产生高水平的
具有早期Th17极化的炎性细胞因子IL-17和IL-2218,19被认为是IAV的关键
在小鼠模型中,IL-23对Th17通路的异常和/或晚期激活被认为损害了病毒的免疫应答。
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天在所有动物中证实肺炎。在妊娠NHP中,流感疾病评分
高于非妊娠动物,并伴有显著的肺外器官损伤(心肌炎、白色物质损伤)。
妊娠NHP在全血和PBMC偶联中几乎不存在早期Th17 CD4 + T细胞应答,
与未怀孕的动物相比,在免疫病理学高峰时肺中的Th17细胞显著增加。
肺和支气管肺泡灌洗液(BAL)中的炎性细胞因子和趋化因子也高于对照组。
妊娠与非妊娠动物。在目标1中,将对非妊娠和妊娠猪尾猕猴进行攻毒
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细胞的频率和广谱免疫相关性,
先天性/适应性免疫应答(即免疫细胞亚群,细胞因子/趋化因子,I/III型干扰素)的
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、NLRP 3炎性小体活化、CD8 + T细胞)。在目标2中,我们将使用bulk
和单细胞RNA测序,以确定PBMC、BAL、肺和胎盘内转录组的变化,
重点是Th17转录网络和抗病毒先天免疫途径。总之,初步数据
表明妊娠动物中异常的Th17应答,这对促进病毒清除至关重要,
防止肺损伤。这些研究将首次全面分析先天/适应性免疫反应
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
这些研究对于IAV大流行的准备是至关重要的,从而能够测试新的UFV的功效和安全性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
KRISTINA M. ADAMS WALDORF其他文献
KRISTINA M. ADAMS WALDORF的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('KRISTINA M. ADAMS WALDORF', 18)}}的其他基金
JAK-STAT Control of Zika Virus-Induced Fetal Injury
JAK-STAT 控制寨卡病毒引起的胎儿损伤
- 批准号:
10321508 - 财政年份:2021
- 资助金额:
$ 86.4万 - 项目类别:
Targeted Inhibition of Interleukin-1 beta to Prevent Preterm Birth
靶向抑制白细胞介素 1 β (IL-1 beta) 预防早产
- 批准号:
10617680 - 财政年份:2020
- 资助金额:
$ 86.4万 - 项目类别:
Targeted Inhibition of Interleukin-1 beta to Prevent Preterm Birth
靶向抑制白细胞介素 1 β (IL-1 beta) 预防早产
- 批准号:
10162632 - 财政年份:2020
- 资助金额:
$ 86.4万 - 项目类别:
Targeted Inhibition of Interleukin-1 beta to Prevent Preterm Birth
靶向抑制白细胞介素 1 β (IL-1 beta) 预防早产
- 批准号:
10400199 - 财政年份:2020
- 资助金额:
$ 86.4万 - 项目类别:
JAK-STAT Control of Zika Virus-Induced Fetal Injury
JAK-STAT 控制寨卡病毒引起的胎儿损伤
- 批准号:
10189500 - 财政年份:2019
- 资助金额:
$ 86.4万 - 项目类别:
Immune Control of Group B Streptococcal Placental
B 族链球菌胎盘的免疫控制
- 批准号:
10463639 - 财政年份:2019
- 资助金额:
$ 86.4万 - 项目类别:
JAK-STAT Control of Zika Virus-Induced Fetal Injury
JAK-STAT 控制寨卡病毒引起的胎儿损伤
- 批准号:
10668233 - 财政年份:2019
- 资助金额:
$ 86.4万 - 项目类别:
JAK-STAT Control of Zika Virus-Induced Fetal Injury
JAK-STAT 控制寨卡病毒引起的胎儿损伤
- 批准号:
10441333 - 财政年份:2019
- 资助金额:
$ 86.4万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 86.4万 - 项目类别:
Grant-in-Aid for Early-Career Scientists