Role of type I IFN and human TLR4 in Coxiella burnetii pathogenesis

 描述(申请人提供)：伯氏柯克斯体是一种专性细胞内病原体，也是Q热的原因。家畜是主要的宿主，因此，参与处理动物的人有自然感染的风险。由于伯氏梭菌具有很高的传染性，并且在环境中仍然具有传染性，它过去曾被武器化，目前是一个生物恐怖主义风险。伯氏卡氏杆菌的内毒素结构是一种已知的毒力因子及其相互作用 伯氏梭菌与脂多糖受体Toll样受体4(TLR4)之间的关系已被多个小组研究。小鼠和人的TLR4与内毒素的结合不同，对某些激动剂的功能反应也不同。例如，来自鼠疫耶尔森菌的低酰化的脂多糖在小鼠细胞中诱导强烈的炎症反应，但在人类细胞中抑制这种反应。伯氏华支睾吸虫的脂多糖同样是低酰化的，并抑制人单核/巨噬细胞的炎症，然而这一点尚未在体内进行检验。我们利用一种新的人TLR4/MD2转基因小鼠来证明人TLR4(HTLR4)相对于小鼠TLR4(MTLR4)增强了伯氏弧菌的感染。I型干扰素信号通路是天然保护机体免受病毒和多种细菌感染的重要途径，其中嗜肺军团菌与伯氏杆菌关系密切。我们最近发现，I型干扰素信号不是促进对伯氏梭菌的保护，而是促进由伯氏梭菌诱导的疾病。这项建议的目的是调查hTLR4表达的小鼠的易感性增强和I型干扰素信号之间的潜在联系。将检验以下假设：I型干扰素促进表达人TLR4的小鼠的伯氏弧菌致病作用。将追求以下特定目标：特定目标1)确定I型干扰素信号在hTLR4/MD2小鼠中对伯氏梭菌病程的影响。具体目的2)确定I型干扰素信号在hTLR4/MD2小鼠产生允许和限制性巨噬细胞亚群中的作用。在这个项目的结束时，我们将描述一种具有开发用于Q热的新疗法的潜力的先天免疫途径。由于新的hTLR4/MD2小鼠模型，结果将更容易转化为人类疾病。

 DESCRIPTION (provided by applicant): Coxiella burnetii is an obligate intracellular pathogen and the cause of Q fever. Domestic animals are the primary reservoir, thus, people involved in animal handling are at risk of natural infection. Because C. burnetii is highly infectious and remains infectious in the environment, it has been weaponized in the past, and is a current bioterrorism risk. The LPS structure of C. burnetii is a known virulence factor and the interaction between C. burnetii and the LPS receptor, toll like receptor 4 (TLR4), has been studied by multiple groups. Mouse and human TLR4s bind LPS differently, and the functional responses are distinct in response to some agonists. For example, hypoacylated LPS from Yersinia pestis induces robust inflammatory responses in mouse cells, but dampens such responses in human cells. The LPS of C. burnetii is similarly hypoacylated and suppresses inflammation in human monocytes/macrophages, however this has not been examined in vivo. We utilized a novel human TLR4/MD2 transgenic mouse to demonstrate that human TLR4 (hTLR4) enhances infection with C. burnetii relative to mouse TLR4 (mTLR4). Type I interferon (IFN) signaling is an important pathway for innate protection from infection with viruses and many bacteria, such as Legionella pneumophila, which is closely related to C. burnetii. We have recently found that rather than promoting protection from C. burnetii, type I IFN signaling promotes disease induced by C. burnetii. The intent of this proposal is to investigate the potential link between enhanced susceptibility of hTLR4-expressing mice and type I IFN signaling. The following hypothesis will be tested: Type I IFN promotes C. burnetii pathogenesis in mice expressing human TLR4. The following Specific Aims will be pursued: Specific Aim 1) Determine the impact of type I IFN signaling in the disease course for C. burnetii in hTLR4/MD2 mice. Specific Aim 2) Determine the role of type I IFN signaling in the generation of permissive and restrictive macrophage subsets in hTLR4/MD2 mice. At the conclusion of this project we will have characterized an innate immune pathway that has potential for development of novel therapeutics for use in Q fever. Because of the novel hTLR4/MD2 mouse model, the results will be more readily translated to human disease.