Elucidating Mechanisms of Mucosal Immune Protection Against Respiratory Syncytial Virus in Infants

阐明婴儿呼吸道合胞病毒粘膜免疫保护机制

• 批准号: 10733663
• 负责人: Stephania A Cormier
• 金额: $ 58.64万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-11 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733663
• 关键词: 1 year old; 5 year old; Address; Adult; Age; Age Months; Antibodies; Antibody Response; Asthma; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Blood; Bronchiolitis; Cell Maturation; Cessation of life; Child; Childhood; Chronic lung disease; Clinical; Communities; Cyclophilins; Data; Dendritic Cells; Development; Disease; Failure; Formalin; Frequencies; Genetic Transcription; Hospitalization; Hospitals; Human; Immune; Immune Targeting; Immune response; Immune system; Immunoglobulin A; Immunoglobulin Class Switching; Infant; Infant Mortality; Infection; Interferon Type I; Interferon alpha; Interferons; Interleukin-10; Investigation; Knowledge; Life; Ligands; Literature; Lower respiratory tract structure; Lymphocyte; Lymphocyte Suppression; Mediating; Membrane; Methodology; Mucosal Immune Responses; Mucous Membrane; Mus; Neonatal; Nose; Phenotype; Play; Pneumonia; Production; Proliferating; Regulation; Research Personnel; Respiratory Mucosa; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory System; Respiratory Tract Diseases; Respiratory Tract Infections; Respiratory syncytial virus; Risk; Role; Sampling; Severities; Severity of illness; Signal Transduction; Structure of mucous membrane of nose; Supplementation; Therapeutic; Time; Umbilical Cord Blood; United States; Upper respiratory tract; Vaccination; Vaccine Design; Vaccine Therapy; Vaccinee; Vaccines; Viral Pathogenesis; Viral Respiratory Tract Infection; Virus; Virus Diseases; Work; adaptive immunity; age related; aspirate; cohort; infancy; infant infection; innovation; mouse model; neonatal infection; neonatal mice; neonate; novel; prevent; programs; respiratory; response; single-cell RNA sequencing; therapy development; transcriptomics; vaccine development

PROJECT SUMMARY/ABSTRACT: Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract viral infection in infants and is responsible for ~60,000 in-hospital deaths annually, with most deaths occurring in infants less than three months of age. Reinfections are common, and those who develop severe bronchiolitis are at further risk of developing chronic lung diseases such as asthma. Past efforts to prevent RSV infection in infants through vaccination with formalin-inactivated virus were disastrous resulting in 80% of vaccinees being hospitalized following community-acquired RSV infection. This has hampered RSV vaccine development for nearly 50 years. We, and other researchers, have used neonatal (i.e., <7d of age) mouse models of RSV infection to mimic the disease in human infants. Recently, we have shown that type I interferon (IFN-I) responses are deficient in neonatal mice, which is consistent with findings in human infants. As repeated infections are indicative of insufficient adaptive immunity, we assessed antibody responses and demonstrated that, congruent with deficiencies in IFN-I, neonatal mice and infants fail to produce RSV-specific IgA. We identified a mechanistic relationship between these components by demonstrating that IgA production requires IFNα in mice. This is especially important, because RSV-specific IgA responses correlate significantly with protection from disease and, in contrast to adults, infants and neonatal mice fail to mount such responses upon infection. IFNα administration in neonatal mice induced RSV-specific IgA production and decreased RSV disease severity. Importantly, neonatal B regulatory lymphocytes (nBregs) expressing IL10, but not IgA, have been observed in RSV-infected infants and neonatal mice in a time-frame consistent with decreased IFN-I levels. Together, these findings guide our hypothesis that failure to develop protective IgA responses in the respiratory mucosa is responsible for RSV severity. We will explore the validity of this hypothesis using unique sample sets from human infant RSV infection cohorts and age-relevant mouse models with three specific aims. Aim 1 will demonstrate that the inability of infants to induce mucosal RSV-specific IgA in response to RSV infection is responsible for enhanced disease severity. Aim 2 will determine whether failure to induce BAFF/APRIL hinders the development of IgA responses to RSV in infants. Aim 3 will establish that nBregs suppress RSV-specific IgA production in infants. The idea that age-dependent regulation of type I IFN regulates the development of protective IgA responses in the respiratory mucosa following RSV infection is novel. We will employ innovative methodologies including single-cell RNAseq (scRNASeq) on B-cell subsets in samples from RSV-infected infants and spatial transcriptomics in samples from RSV-infected neonatal mice to characterize Breg phenotypes, transcriptional programs, and local functions. Data derived from these studies will have a positive paradigm-shifting impact on the understanding of severe RSV disease and yield novel immunological targets to advance pediatric vaccine design.

项目概要/摘要： 呼吸道合胞病毒（RSV）是婴儿下呼吸道病毒感染的第一大原因 每年造成约 60,000 例院内死亡，其中大多数死亡发生在不到 10 岁的婴儿中 三个月大时，再感染很常见，而患有严重细支气管炎的人则面临更大的风险。 过去通过预防婴儿 RSV 感染的努力。 福尔马林灭活病毒疫苗接种是灾难性的，导致 80% 的疫苗需要住院治疗 社区获得性 RSV 感染导致近 50 年来 RSV 疫苗的开发受到阻碍。 我们和其他研究人员已经使用 RSV 感染的新生儿（即 <7 天）小鼠模型来进行研究。 最近，我们已经证明 I 型干扰素 (IFN-I) 反应是 新生小鼠中存在缺陷，这与人类婴儿中的发现一致，因为重复感染是存在的。 适应性免疫不足的指标，我们评估了抗体反应并证明， 与 IFN-I 缺陷一致，新生小鼠和婴儿无法产生 RSV 特异性 IgA。 通过证明 IgA 的产生需要 IFNα 来揭示这些成分之间的机制关系 这一点尤其重要，因为 RSV 特异性 IgA 反应与保护显着相关。 与成人相比，婴儿和新生小鼠在感染后无法产生这种反应。 新生小鼠中使用 IFNα 可诱导 RSV 特异性 IgA 产生并减少 RSV 疾病 重要的是，表达 IL10（而非 IgA）的新生儿 B 调节性淋巴细胞 (nBreg) 已受到影响。 在 RSV 感染的婴儿和新生小鼠中观察到这一现象，时间范围与 IFN-I 水平下降一致。 总之，这些发现指导了我们的假设，即未能在体内产生保护性 IgA 反应。 呼吸道粘膜与 RSV 严重程度有关，我们将使用该方法来探讨这一假设的有效性。 来自人类婴儿 RSV 感染队列和年龄相关小鼠模型的独特样本集，具有三个 具体目标 1 将证明婴儿无法在体内诱导粘膜 RSV 特异性 IgA。 对 RSV 感染的反应是导致疾病严重程度增加的原因，目标 2 将决定是否未能做到这一点。 诱导 BAFF/APRIL 阻碍婴儿对 RSV 的 IgA 反应，目标 3 将确定这一点。 nBregs 抑制婴儿 RSV 特异性 IgA 的产生 I 型 IFN 的年龄依赖性调节。 RSV 感染后调节呼吸道粘膜中保护性 IgA 反应的发展 我们将采用创新方法，包括对 B 细胞亚群进行单细胞 RNAseq (scRNASeq)。 RSV 感染婴儿的样本和 RSV 感染的新生小鼠样本的空间转录组学 表征 Breg 表型、转录程序和来自这些研究的数据。 将对严重 RSV 疾病的理解产生积极的范式转变影响并产生新的成果 推进儿科疫苗设计的免疫学目标。

项目成果

Deficiency in ST2 signaling ameliorates RSV-associated pulmonary hypertension.

ST2 信号传导缺陷可改善 RSV 相关的肺动脉高压。

• 发表时间: 2021
• 作者: Vu, Luan D;Saravia, Jordy;Jaligama, Sridhar;Baboeram Panday, Rajshri V;Sullivan, Ryan D;Mancarella, Salvatore;Cormier, Stephania A;Kimura, Dai
• 通讯作者: Kimura, Dai

IL-1β Promotes Expansion of IL-33+ Lung Epithelial Stem Cells after Respiratory Syncytial Virus Infection during Infancy.

IL-1β 促进婴儿期呼吸道合胞病毒感染后 IL-33 肺上皮干细胞的扩增。

• 发表时间: 2022-03
• 影响因子: 6.4
• 作者: Vu, Luan D;Phan, Anh T Q;Hijano, Diego R;Siefker, David T;Tillman, Heather;Cormier, Stephania A
• 通讯作者: Cormier, Stephania A

5-HT2 receptor activation alleviates airway inflammation and structural remodeling in a chronic mouse asthma model.

• DOI: 10.1016/j.lfs.2019.116790
• 发表时间: 2019-11-01
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Thomas W. Flanagan;Melaine N. Sebastian;Diana M. Battaglia;T. Foster;S. Cormier;C. Nichols
• 通讯作者: C. Nichols

Innate IL-13 in virus-induced asthma?

先天性 IL-13 与病毒诱发的哮喘有关？

• 发表时间: 2011-06-20
• 影响因子: 30.5
• 作者: Cormier, Stephania A;Kolls, Jay K
• 通讯作者: Kolls, Jay K

Prolonged viral replication and longitudinal viral dynamic differences among respiratory syncytial virus infected infants.

呼吸道合胞病毒感染婴儿的病毒复制时间延长和纵向病毒动态差异。

• 发表时间: 2017-11
• 影响因子: 3.6
• 作者: Brint, Monica E;Hughes, Joshua M;Shah, Aditya;Miller, Chelsea R;Harrison, Lisa G;Meals, Elizabeth A;Blanch, Jacqueline;Thompson, Charlotte R;Cormier, Stephania A;DeVincenzo, John P
• 通讯作者: DeVincenzo, John P