Preterm birth, lung innate immunity, and RSV

早产、肺部先天免疫和 RSV

• 批准号: 7559729
• 负责人: Mark R Ackermann
• 金额: $ 46.66万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559729
• 关键词: Admission activity; Affect; Age; Alveolar Macrophages; Alveolus; Animal Diseases; Antigen-Presenting Cells; Area; Biological; Biological Assay; Birth; Cell Proliferation; Cells; Child; Clinical; Clinical Pathology; Collaborations; Computer Analysis; Cultured Cells; Cytokine Gene; Data; Defensins; Dendritic Cells; Dentistry; Electronic Mail; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Funding; Gene Expression; Gene Expression Profiling; Gene Proteins; Gene Targeting; Genes; Genetic Transcription; Goals; Grant; Growth; Hospitalization; Human; IL8 gene; Immune; Immune response; Immunity; Infant; Infection; Intensive Care Units; Interferon-alpha; Interleukin-10; Lesion; Lung; Lung diseases; Manuscripts; Mechanical ventilation; Medical; Medicine; Modeling; Molecular Profiling; National Institute of Allergy and Infectious Disease; Natural Immunity; Orthologous Gene; Outcome; Oxygen; Peptides; Persons; Predisposition; Pregnancy; Premature Birth; Premature Infant; Principal Investigator; Production; Proliferating; Proteins; Publishing; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; RNA Interference; Recording of previous events; Regulator Genes; Research; Research Personnel; Research Project Grants; Respiratory Syncytial Virus Infections; Respiratory System; Respiratory syncytial virus; Respiratory tract structure; Role; Ruminants; Scientist; Severities; Severity of illness; Sheep; Site; Structure of respiratory epithelium; Telephone; Testing; Tissues; Type II Epithelial Receptor Cell; United States National Institutes of Health; Vascular Endothelial Growth Factors; Veterinarians; Veterinary Medicine; Viral; Virus Activation; Virus Diseases; Work; antimicrobial; antimicrobial peptide; base; beta-Defensins; bronchial epithelium; college; cytokine; effective therapy; experience; human DEFB1 protein; human disease; in vitro Model; in vitro testing; in vivo; interleukin-12 subunit p35; laser capture microdissection; meetings; novel; pathogen; pediatrician; prevent; programs; release factor; respiratory; response; surfactant; toll-like receptor 4

DESCRIPTION (provided by the applicant): Respiratory syncytial virus (RSV) infection is the most common cause of respiratory disease leading to hospitalization in children. Preterm infants are especially susceptible to severe RSV infection. Respiratory epithelium is an initial site of RSV infection and epithelial cells along with alveolar macrophages (AM) and dendritic cells (DC) are vital to innate and adaptive immune responses. However, the extent of innate immune gene expression by epithelia and AM-DC in preterm infants can be variable/limited. The hypothesis is that: Reduced innate immunity by respiratory epithelia and AM-DC preterm enhances susceptibility to RSV infection This hypothesis is based on the facts above and our preliminary data in lambs demonstrating limited expression of surfactant proteins A and D (SP-AD), sheep beta-defensin-1 (SBD-1), and Toll-like receptor 4 (TLR4) preterm. It will be tested in preterm lambs which have close similarities with human disease including susceptibility, lesions, and innate immunity. Specific Aim 1 compares expression of key innate immune genes (SBD-1, SP-AD, TLR4) and protein/peptide production in vivo as well as AM-DC cytokine expression in pre- and full-term lung. It also tests the hypothesis that limited epithelial cell proliferation and/or differentiation pre-term underlie(s) the mechanistic basis for limited SP-AD, SDB-1 expression and tests this by comparing transcriptional activity, protein/peptide production in pre- and full term cultured cells with or without cell proliferation and differentiation. Specific Aim 2 tests the hypothesis that SP-AD, SBD-1 and AM-DC responses to RSV are less at pre- than full-term in the lamb model and in vitro with cultured epithelial cells. A second hypothesis, that increased cell proliferation and/or differentiation of epithelia protects against RSV infection, will be tested in vitro with treatments from Aim 1. The extent to which SP-AD, SBD-1 directly prevent RSV infection will be tested with RNAi assays. Specific Aim 3 tests the hypothesis that yet other innate immune genes expressed with cell proliferation/differentiation prevent RSV infection. This Aim uses gene expression profiling of primary polarized human lung cells and a respiratory epithelia-specific probe set (Unigene) that is the most well-annotated and defined gene target set to date. It also identifies ovine orthologs of human genes and test for impaired/reduced expression preterm. This team combines veterinary and human medical expertise to attain the goal of this project: to discover the reason(s) for inadequate expression of SP-AD, SBD-1 and other innate immune genes as well as AMDC responses at preterm that predispose to RSV infection. The work is significant because it discovers the underlying basis for RSV susceptibility preterm and mechanistic approaches to enhance innate immunity.

描述（由申请方提供）：呼吸道合胞病毒（RSV）感染是导致儿童住院的呼吸道疾病的最常见原因。早产儿特别容易受到严重的RSV感染。呼吸道上皮是RSV感染的起始部位，上皮细胞沿着肺泡巨噬细胞（AM）和树突状细胞（DC）对于先天性和适应性免疫应答至关重要。然而，早产儿中上皮细胞和AM-DC的先天免疫基因表达的程度可能是可变的/有限的。假设是：呼吸道上皮细胞和AM-DC早产儿先天免疫力降低增强了对RSV感染的易感性。该假设基于上述事实和我们在羔羊中的初步数据，表明早产儿表面活性蛋白A和D（SP-AD）、绵羊β-防御素-1（SBD-1）和Toll样受体4（TLR 4）的表达有限。将在与人类疾病（包括易感性、病变和先天免疫）密切相似的早产羔羊中进行试验。具体目标1比较了体内关键先天免疫基因（SBD-1、SP-AD、TLR 4）的表达和蛋白质/肽的产生，以及早产和足月肺中AM-DC细胞因子的表达。本发明还检验了以下假设：有限的上皮细胞增殖和/或分化早产是有限的SP-AD、SDB-1表达的机制基础，并通过比较有或没有细胞增殖和分化的早产和足月培养细胞中的转录活性、蛋白质/肽产生来检验这一点。具体目标2检验了以下假设：在羔羊模型中和体外培养的上皮细胞中，SP-AD、SBD-1和AM-DC对RSV的反应在足月前比足月时更低。第二个假设，即上皮细胞的细胞增殖和/或分化增加可防止RSV感染，将在体外用目标1的治疗进行测试。SP-AD、SBD-1直接预防RSV感染的程度将用RNAi测定法进行测试。特异性目的3检验了以下假设：与细胞增殖/分化一起表达的其他先天免疫基因可预防RSV感染。该目的使用原代极化人肺细胞的基因表达谱和呼吸道上皮特异性探针集（Unigene），该探针集是迄今为止注释最好和定义最明确的基因靶点集。它还鉴定了人类基因的绵羊直系同源物，并检测了早产儿表达受损/降低。该团队结合了兽医和人类医学专业知识，以实现该项目的目标：发现SP-AD，SBD-1和其他先天免疫基因表达不足的原因，以及早产时易患RSV感染的AMDC反应。这项工作是重要的，因为它发现了RSV易感性的基础，早产和机制的方法，以提高先天免疫。

项目成果

Exogenous administration of vascular endothelial growth factor prior to human respiratory syncytial virus a2 infection reduces pulmonary pathology in neonatal lambs and alters epithelial innate immune responses.

• DOI: 10.3109/01902148.2010.484518
• 发表时间: 2011-04
• 期刊: Experimental lung research
• 影响因子: 1.7
• 作者: Olivier AK;Gallup JM;van Geelen A;Ackermann MR
• 通讯作者: Ackermann MR

Human respiratory syncytial virus A2 strain replicates and induces innate immune responses by respiratory epithelia of neonatal lambs.

• DOI: 10.1111/j.1365-2613.2009.00643.x
• 发表时间: 2009-08
• 期刊: International journal of experimental pathology
• 影响因子: 3
• 作者: Olivier A;Gallup J;de Macedo MM;Varga SM;Ackermann M
• 通讯作者: Ackermann M

SPUD qPCR assay confirms PREXCEL-Q softwares ability to avoid qPCR inhibition.

SPUD qPCR 测定证实了 PREXCEL-Q 软件避免 qPCR 抑制的能力。

• 发表时间: 2010
• 期刊: Current issues in molecular biology
• 影响因子: 3.1
• 作者: Gallup,JM;Sow,FB;VanGeelen,A;Ackermann,MR
• 通讯作者: Ackermann,MR

Ontogeny of the immune response in the ovine lung.

绵羊肺免疫反应的个体发育。

• DOI: 10.3109/08820139.2011.631657
• 发表时间: 2012
• 期刊: Immunological investigations
• 影响因子: 2.8
• 作者: Sow,FatoumataB;Gallup,JackM;Derscheid,Rachel;Krishnan,Subramaniam;Ackermann,MarkR
• 通讯作者: Ackermann,MarkR

Laser Capture Microdissection Revisited as a Tool for Transcriptomic Analysis: Application of an Excel-Based qPCR Preparation Software (PREXCEL-Q).

重新审视激光捕获显微切割作为转录组分析工具：基于 Excel 的 qPCR 制备软件 (PREXCEL-Q) 的应用。

• 发表时间: 2009
• 期刊: International journal of biomedical science : IJBS
• 作者: Sow,FatoumataB;Gallup,JackM;Sacco,RandyE;Ackermann,MarkR
• 通讯作者: Ackermann,MarkR