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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 类鼻疽病是一种传染病，由接触假性伯克霍尔德氏菌引起，这种腐生植物主要发现于东南亚和澳大利亚北部。类鼻疽被认为是一种新出现的传染病和人畜共患病原体。在过去的十年中，在流行地区，假鼻疽相关性细菌性败血症和支气管肺炎的发病率显著增加。假鼻疽杆菌是一种生物威胁因子，主要是因为它在低剂量(不到100个细菌细胞)下具有显着的传染性。因此，疾病控制和预防中心(CDC)已将假鼻疽杆菌确定为一种精选的生物制剂，具有对群众滥用的高可能性。 类鼻疽病是一种严重的临床综合征，部分取决于暴露途径、剂量和宿主的免疫状态，尽管疾病的发病机制仍不清楚。虽然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。 对类鼻疽的发病机制的破译仍在继续；TLRs在介导感染和促进细胞内进入方面的作用尤为重要。我们将三个品系的小鼠(BALB/c、C57BL/6或TLR-4 KO转基因小鼠(C3H-HeJ))雾化吸入泰兰白僵菌，以进一步确定Th1相关宿主反应的作用。结果表明，TLR-4在伯克霍尔德氏菌相关感染中可能不起重要作用，泰兰伯克霍尔德氏菌可作为实验室研究类鼻疽小动物模型的替代物，并为建立假鼻疽非人类灵长类动物感染模型提供重要信息。 随后，我们利用这个小鼠模型评估了候选疫苗对伪马利氏杆菌的保护效果。我们检测了延长因子Tu(EF-Tu)作为假性鼻炎杆菌疫苗的免疫原性。免疫小鼠在接种EF-Tu疫苗后2周，气雾剂攻击致死剂量的泰兰伯氏杆菌。REF-Tu免疫诱导小鼠的抗原特异性抗体和CMI反应，并减少雾化泰兰白僵菌攻击的小鼠的肺部细菌负荷和促炎细胞因子。以粘膜表面为靶点并诱导1型反应的疫苗策略可能会加强对假鼻疽气雾剂感染的保护。