NONHUMAN PRIMATE MODEL OF MELIODOSIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 类鼻疽是一种由暴露于类鼻疽伯克霍尔德氏菌引起的传染病，类鼻疽伯克霍尔德氏菌是一种主要在东南亚和北方澳大利亚发现的寄生虫。 类鼻疽被认为是一种新兴的传染病和动物流行病。B的发生率。在过去十年中，假鼻疽相关的细菌性脓毒症和支气管肺炎在流行地区显著增加。B。鼻疽假单胞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）下具有显著的感染性。因此，疾病控制和预防中心（CDC）已经确定了B。作为一种选定的生物制剂，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，部分依赖于暴露途径、剂量和宿主的免疫状态，尽管该疾病的发病机制仍不清楚。 虽然皮下接种引起的感染并不少见，但吸入引起的疾病最严重。 阐明类鼻疽的发病机制仍在继续发展; TLR在介导感染和促进细胞内进入中的作用特别重要。 我们将三种品系的小鼠（BALB/c、C57 BL/6或TLR-4 KO转基因（C3 H-Hej））暴露于雾化的B。thailandensis进一步定义了Th 1相关宿主应答的作用。 结果提示TLR-4在伯克霍尔德氏菌相关感染中可能不起显著作用，而B. thailandensis可用作小动物模型中类鼻疽实验室研究的替代剂，并为定义B的非人灵长类动物模型提供关键信息。类鼻疽感染。 我们随后利用这种鼠模型来评估候选疫苗对B的保护效力。假鼻疽 我们测试了延伸因子Tu（EF-Tu）作为B的潜在疫苗的免疫原性。假鼻疽 在用EF-Tu接种后两周，用致死剂量的B攻击免疫小鼠。用喷雾器喷泰国大麻。 rEF-Tu免疫诱导小鼠抗原特异性抗体和CMI应答，并降低雾化B激发的小鼠肺细菌负荷和促炎细胞因子。泰国茶靶向粘膜表面并诱导1型反应的疫苗策略可提供增强的保护，以对抗B的气溶胶感染。假鼻疽

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.