Immune Determinants to Bacterial and Viral Co-Infection

细菌和病毒合并感染的免疫决定因素

• 批准号: 6606309
• 负责人: Luis J Montaner
• 金额: $ 24.89万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6606309
• 关键词: CD antigens; Mycobacterium bovis; active immunization; antigen presenting cell; antiviral antibody; bacterial RNA; bacterial genetics; bactericidal immunity; cell proliferation; comorbidity; dendritic cells; enzyme linked immunosorbent assay; flow cytometry; gene expression; host organism interaction; immunologic memory; influenza; laboratory mouse; leukocyte activation /transformation; leukocyte adhesion molecules; lymphocyte; microarray technology; microorganism culture; outcomes research; viral vaccines; virus genetics

DESCRIPTION (provided by applicant): The long-range goal of this application is to determine the factors that predict the manner in which pathogenesis develops during poly-microbial infections. The short-term goal of this project will be to determine the manner in which BCG-associated inflammation and its modulation of antigen presenting cells affects a new immune response to a vaccine antigen delivered as and inactivated organism. Our preliminary studies support our goals and application by establishing a link between innate DC dysfunction and lower adaptive responses to vaccine antigens delivered as an inactivated organism during an ongoing bacterial infection. Based on our preliminary observations, we hypothesize that a decreased potential to develop protective immune responses during Mycobacterial infection is due to a cyclic period of down-regulation of accessory cell function and a decrease of CD11c cell subsets. We will test this hypothesis by defining immune correlates and gene expression patterns within CD11c+ and CD11b+ accessory cell subsets during BCG infection through [1] longitudinal analysis of the changes in B-cell proliferation, T -cell activation, DC cell subsets, DC activation (CD86, CD80, CD40, CD95, MHC-II) and function (MLR, endocytosis, TLR-4 induced IL-12p70, IL-I0, TNF-a secretion), and RNA gene expression of sorted CD11c+CD11b+ or CD 11c+CD 11 b+ DC subsets from longitudinal time points by cDNA microarrays of un-stimulated and in vitro stimulated cultures; and [2] establishing the biological impact of accessory cell changes due to primary BCG infection on the development of secondary anti-flu responses by analysis of the development and recruitment of antiviral humoral and cell-mediated immune memory responses acquired through UV inactivated Influenza A/PR8 vaccination of naive or BCG-infected animals at weekly intervals throughout BCG infection. We apply a vaccine approach within an on-going bacterial infection as a surrogate method to elicit a primary immune response and its associated memory pools with minimal pathology or additional pathogen co-factors. We will compare morbidity and mortality outcomes to developing antiviral immune responses following live challenge of animals having received vaccination against Influenza A/PR8 at different periods of BCG infection and clearance. Completion of this application will provide identify innovative targets for increased susceptibility to bacterial/viral co-infections by addressing understudied areas of innate immunity and chronic inflammation as central factors to decreased adaptive responses and protective immunity. This application represents a collaborative effort by The Wistar Institute and the Department of Dermatology, and the Center for Clinical Epidemiology and Biostatistics from the University of Pennsylvania.

描述（由申请人提供）： 该应用的长期目标是确定预测多种微生物感染期间发病机制发展方式的因素。该项目的短期目标是确定卡介苗相关炎症及其对抗原呈递细胞的调节如何影响对作为灭活生物体传递的疫苗抗原的新免疫反应。我们的初步研究通过建立先天性 DC 功能障碍和对持续细菌感染期间作为灭活有机体传递的疫苗抗原的较低适应性反应之间的联系来支持我们的目标和应用。 根据我们的初步观察，我们假设分枝杆菌感染期间产生保护性免疫反应的潜力下降是由于辅助细胞功能下调和 CD11c 细胞亚群减少的周期性周期所致。 我们将通过 [1] 对 B 细胞增殖、T 细胞激活、DC 细胞亚群、DC 激活的变化进行纵向分析，定义 BCG 感染期间 CD11c+ 和 CD11b+ 辅助细胞亚群内的免疫相关性和基因表达模式，从而检验这一假设。 CD86、CD80、CD40、CD95、MHC-II) 和功能（MLR、内吞作用、TLR-4 诱导的 IL-12p70、IL-10、TNF-a）分泌），以及通过未刺激和体外刺激培养物的 cDNA 微阵列从纵向时间点分选的 CD11c+CD11b+ 或 CD 11c+CD 11b+ DC 子集的 RNA 基因表达； [2] 通过分析通过紫外线灭活甲型流感获得的抗病毒体液和细胞介导的免疫记忆反应的发展和募集，确定原发性卡介苗感染引起的辅助细胞变化对继发性抗流感反应发展的生物学影响/在 BCG 感染期间，每周对初次接触或感染 BCG 的动物进行 PR8 疫苗接种。 我们在正在进行的细菌感染中应用疫苗方法作为替代方法，以引起初级免疫反应及其相关的记忆库，并具有最小的病理学或额外的病原体辅因子。 我们将比较在 BCG 感染和清除的不同时期接受 A/PR8 流感疫苗接种的动物在活体攻击后产生抗病毒免疫反应的发病率和死亡率结果。 该申请的完成将通过解决先天免疫和慢性炎症的未充分研究领域作为降低适应性反应和保护性免疫的核心因素，为增加细菌/病毒混合感染的易感性提供确定的创新目标。该应用程序是 Wistar 研究所和皮肤病学系以及宾夕法尼亚大学临床流行病学和生物统计学中心的合作成果。