Mucosal and Systemic Immune Responses to Influenza Virus

对流感病毒的粘膜和全身免疫反应

• 批准号: 9188802
• 负责人: Harry Bernard Greenberg
• 金额: $ 42.79万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188802
• 关键词: Acute; Address; Adult; Age-Years; Antibodies; Antibody Formation; Antibody Response; Attenuated; Avian Influenza; B-Lymphocytes; Blood; Blood Cells; Blood specimen; Cells; Child; Clinical; Clinical Research; Collaborations; Communities; Data; Development; Epithelial; Epithelial Cells; Extramural Activities; Flow Cytometry; Flu virus; Gene Expression Profile; Genetic Transcription; Genome; Goals; Healthcare Systems; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Markers; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A virus; Influenza vaccination; Innate Immune Response; Innate Immune System; Knowledge; Leukocytes; Lymphocyte; Measurement; Measures; Microfluidics; Mucosal Immune Responses; Mucous Membrane; Nasal Epithelium; National Institute of Allergy and Infectious Disease; Natural Immunity; Nose; Pathogenicity; Patients; Peripheral; Plasmablast; Population; Quantitative Reverse Transcriptase PCR; Research; Research Personnel; Route; Sampling; Serological; Serum; Site; Structure of mucous membrane of nose; Study Subject; Swab; System; Technology; Testing; Time; United States National Institutes of Health; Upper respiratory tract; Vaccines; Viral; Virulence; Virus; Virus Diseases; Virus Replication; adaptive immune response; adaptive immunity; cell type; fighting; flu; healthy volunteer; immunogenicity; improved; influenza virus vaccine; influenzavirus; live attenuated influenza vaccine; novel; pandemic disease; pandemic influenza; predictive marker; protective efficacy; public health relevance; response; response biomarker; seasonal influenza

DESCRIPTION (provided by applicant): The 2009 influenza (flu) pandemic caused by the A(H1N1)pdm09 virus and the sporadic human cases of highly pathogenic avian flu A virus infection emphasize the need for improved flu vaccines for both seasonal and potential pandemic flu strains. One approach to flu vaccination entails the nasal administration of live attenuated flu viruses (LAIV), which mimics, in part, the natural route and site of viral infectionin the human nasal epithelial cells (HNEC) of the upper respiratory tract. However, LAIV fail to induce a robust systemic immune response compared to natural wild-type (wt) flu infections, suggesting important differences in the host innate and adaptive immune responses to attenuated and wt viruses. Flu virus replication in HNEC results in the induction of host immune responses within both epithelial and leukocyte cell subsets of the nasal mucosa. On the other hand, flu viruses encode multiple strategies to regulate and suppress the initial host innate response in both a strain- and cell type-specific manner, which is an important determinant of flu pathogenicity. We hypothesize that measurement of (a) early host transcriptional responses to LAIV vs. wt strains in HNEC as well as in mucosal and peripheral lymphocyte populations and (b) peripheral plasmablast B cell and serum and nasal antibody responses from the same individuals will identify specific early immune markers predictive of viral replication, immunogenicity, and ultimately protection. We propose to take advantage of an ongoing flu A(H1N1)pdm09 challenge study at the NIH Clinical Center to test this hypothesis. We will collect two additional nasal swabs from study subjects and sort nasal epithelial and lymphocyte cell populations by flow cytometry for subsequent high-throughput microfluidic qRT-PCR analysis of mucosal immune responses and local viral replication. Blood and nasal wash samples are also being collected from the same individuals to measure peripheral transcriptional responses and systemic B cell and antibody responses. The specific aims are to: 1) Characterize early host immune transcriptional responses in bulk unsorted nasal mucosal cells and sorted HNEC and nasal lymphocyte populations and in peripheral blood cells, to identify common and unique transcriptional signatures induced by wt virus and compare them to the host responses to LAIV immunization, which is being studied with similar approaches in other ongoing studies at Stanford; and 2) Characterize peripheral plasmablast B cell and serum and mucosal antibody responses to wt flu infection at a quantitative level in these same individuals and compare these to other ongoing studies of LAIV at Stanford, to identify local and/or systemic early transcriptional innate immunity response markers that correlate with subsequent plasmablast and other adaptive local and systemic humoral immunity indicators. These studies are expected to generate new knowledge on the underlying mechanism for protective immunity against flu viruses, which will guide the development of improved seasonal and pandemic flu vaccines.

描述（由申请人提供）：由A（H1N1）PDM09病毒引起的2009年流感（流感）大流行，以及高致病性禽流感病毒感染的零星人类病例，强调需要改善季节性和潜在流血流感的流感疫苗。一种流感疫苗接种的方法是鼻施用减毒病毒（LAIV），其中部分模仿了前呼吸道的人类鼻皮细胞（HNEC）的病毒感染的自然途径和部位。然而，与天然野生型（WT）流感感染相比，LAIV无法诱导鲁棒的全身免疫反应，这表明宿主先天和适应性免疫反应对减毒和WT病毒的反应有重要差异。 HNEC中的流感病毒复制导致鼻粘膜上皮细胞和白细胞细胞亚群中宿主免疫反应诱导。另一方面，流感病毒编码多种策略，以特异性方式和细胞类型特异性的方式调节和抑制初始宿主先天反应，这是流感致病性的重要决定因素。我们假设（a）对HNEC，粘膜和外围淋巴细胞群体中的对LAIV与WT菌株的早期宿主转录反应的测量以及（B）（b）外周plasmablast B细胞，血清以及来自同一个体的鼻腔抗体反应将确定特定的早期免疫标记的预测性，可预测病毒性及不受性病，并识别病毒性的良好性。我们建议利用NIH临床中心的持续流感A（H1N1）PDM09挑战研究来检验该假设。我们将通过流式细胞仪从研究对象中收集两个额外的鼻拭子，并通过流式细胞仪进行鼻上皮和淋巴细胞细胞群体，以进行随后的高通量微流体QRT-PCR分析粘膜免疫反应和局部病毒复制。还从相同个体收集了血液和鼻洗样品，以测量周围的转录反应以及全身B细胞和抗体反应。具体目的是：1）表征早期宿主免疫转录反应中的大量未分类的鼻粘膜细胞，排序的HNEC和鼻淋巴细胞群体以及外周血细胞中的早期免疫转录反应，以及在WT病毒中诱导的常见和独特的转录特征，并与宿主对LAIV免疫进行了比较，该方法与宿主进行了相似的反应，该方法与宿主进行了相似的效果，该方法是在其他方面进行的，该方法在其他方面进行了研究，该方法是在其他方面进行的，在其他方面进行了其他研究，该方法在其他方面进行了研究。和2）表征这些相同个体中对WT流感感染对WT流感感染的外围浆质B细胞，血清和粘膜抗体反应，并将其与Stanford的其他正在进行的LAIV研究进行比较，以识别局部和/或系统性的早期转录的先天性免疫反应标记，与随后的层状局部和其他适应性的局部和Systome Primant和Systome andic andic humor和Systemic humor humor humor humor humor humor humor humor humor humor。预计这些研究将产生有关针对流感病毒的保护性免疫机制的新知识，这将指导改善的季节性和大流行流感疫苗的发展。