NONHUMAN PRIMATE MODEL OF MELIODOSIS

非人类灵长类动物鼻根瘤模型

• 批准号: 8172994
• 负责人: CHAD J. ROY
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172994
• 关键词: Aerosols; Animal Model; Antibodies; Antigens; Area; Australia; Biological; Biological Products; Breathing; Bronchopneumonia; Burkholderia; Burkholderia pseudomallei; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Communicable Diseases; Computer Retrieval of Information on Scientific Projects Database; Disease; Dose; Emerging Communicable Diseases; Exposure to; Funding; Grant; Immune; Immune response; Immunization; Inbred BALB C Mice; Incidence; Infection; Inflammatory; Institution; Investigation; Laboratories; Lung; Mediating; Melioidosis; Modeling; Mouse Strains; Mus; Pathogenesis; Peptide Elongation Factor Tu; Play; Research; Research Personnel; Resources; Role; Route; Sepsis; Source; Southeastern Asia; Surface; Syndrome; Testing; Transgenic Organisms; United States National Institutes of Health; Vaccination; Vaccines; aerosolized; cytokine; immunogenicity; nonhuman primate; protective efficacy; response; subcutaneous; vaccine candidate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Melioidosis is an infectious disease caused by exposure to Burkholderia pseudomallei, a saprophyte found primarily in Southeast Asia and Northern Australia. Melioidosis is considered an emerging infectious disease and epizoonotic agent. Incidence of B. pseudomallei-associated bacterial sepsis and bronchopneumonia has significantly increased in endemic areas over the past decade. B. pseudomallei is a biological threat agent primarily because of its remarkable infectivity at a low (less than 100 bacterial cells) dose. As a result, the Centers of Disease Control and Prevention (CDC) have identified B. pseudomallei as a select biological agent, with a high potential for misuse against masses. Melioidosis is associated with a severe clinical syndrome which is dependant in part on the route of exposure, dose, and immune status of the host, although much remains unclear about pathogenesis of the disease. Although infection from subcutaneous inoculation is not uncommon, inhalation produces the most severe disease. Deciphering the pathogenesis of melioidosis continues to evolve; the role of TLRs in mediating infection and facilitating intracellular entry is of particular importance. We exposed three strains of mice (BALB/c, C57BL/6 or TLR-4 KO transgenics (C3H-Hej)) to aerosolized B. thailandensis to further define the role of Th1-associated host response. Results indicated that TLR-4 may not play a prominent role in Burkholderia-related infection, that B. thailandensis can be used as a surrogate agent for experimental laboratory investigation of melioidosis in small animal models, and provide critical information to defining the nonhuman primate model of B. pseudomallei infection. We have subsequently utilized this murine model to assess the protective efficacy of candidate vaccines against B. pseudolmallei. We tested the immunogenicity of Elongation Factor Tu (EF-Tu) as a potential vaccine for B. pseudomallei. Immunized mice were challenged two weeks after vaccination with EF-Tu with a lethal dose of B. thailandensis by aerosol. Immunization with rEF-Tu induced antigen-specific antibody and CMI responses in mice and reduced lung bacterial burden and pro-inflammatory cytokines in mice challenged with aerosolized B. thailandensis. Vaccine strategies that target the mucosal surface and induce Type 1 responses may provide enhanced protection against aerosol infection with B. pseudomallei.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 类鼻疽是一种因接触类鼻疽伯克霍尔德氏菌而引起的传染病，这是一种主要发现于东南亚和澳大利亚北部的腐生菌。 类鼻疽被认为是一种新出现的传染病和人畜共患病病原体。过去十年来，类鼻疽杆菌相关的细菌性败血症和支气管肺炎的发病率在流行地区显着增加。鼻疽伯克氏菌是一种生物威胁因子，主要是因为其在低剂量（少于 100 个细菌细胞）下具有显着的传染性。因此，美国疾病控制与预防中心 (CDC) 已将类鼻疽伯克氏菌确定为一种精选的生物制剂，很可能被滥用于人群。 类鼻疽与严重的临床综合征相关，该综合征部分取决于暴露途径、剂量和宿主的免疫状态，尽管该疾病的发病机制仍不清楚。 尽管皮下接种引起的感染并不少见，但吸入会导致最严重的疾病。 类鼻疽发病机制的解析仍在不断发展； TLR 在介导感染和促进细胞内进入方面的作用尤为重要。 我们将三种小鼠品系（BALB/c、C57BL/6 或 TLR-4 KO 转基因小鼠 (C3H-Hej)）暴露于雾化的泰国芽孢杆菌中，以进一步确定 Th1 相关宿主反应的作用。 结果表明，TLR-4在伯克霍尔德杆菌相关感染中可能并不起显着作用，泰国伯克霍尔德杆菌可作为小动物模型类鼻疽实验实验室研究的替代剂，并为定义鼻疽伯克霍尔德杆菌感染的非人灵长类动物模型提供关键信息。 随后，我们利用该小鼠模型来评估候选疫苗对类鼻疽杆菌的保护功效。 我们测试了伸长因子 Tu (EF-Tu) 作为伪鼻疽伯克氏菌潜在疫苗的免疫原性。 免疫小鼠在用致死剂量的泰国拟杆菌气雾剂接种 EF-Tu 两周后受到攻击。 rEF-Tu 免疫诱导了小鼠的抗原特异性抗体和 CMI 反应，并减少了雾化泰国伯氏杆菌攻击小鼠的肺部细菌负荷和促炎细胞因子。针对粘膜表面并诱导 1 型反应的疫苗策略可能会增强对类鼻疽伯克氏菌气溶胶感染的保护。