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.

项目总结/文摘:

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。

• DOI: 10.1152/ajpheart.00018.2021
• 发表时间: 2021
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Vu,LuanD;Saravia,Jordy;Jaligama,Sridhar;BaboeramPanday,RajshriV;Sullivan,RyanD;Mancarella,Salvatore;Cormier,StephaniaA;Kimura,Dai
• 通讯作者: Kimura,Dai