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

 描述（由申请方提供）：贝氏柯克斯体是一种专性细胞内病原体，是Q热的病因。家畜是主要的宿主，因此，参与动物处理的人有自然感染的风险。因为C.贝氏体具有高度传染性，在环境中仍具有传染性，过去曾被武器化，目前是一种生物恐怖主义风险。C.贝氏体是已知的毒力因子， C.贝氏体和LPS受体Toll样受体4（TLR 4）的作用已经由多个小组进行了研究。小鼠和人TLR 4结合LPS的方式不同，对某些激动剂的功能反应也不同。例如，来自鼠疫耶尔森氏菌的低酰化LPS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。C. Burnetii类似地是低酰化的，并且抑制人单核细胞/巨噬细胞中的炎症，然而这还没有在体内进行检测。我们利用一种新的人TLR 4/MD 2转基因小鼠来证明人TLR 4（hTLR 4）增强了C. Burnetii相对于小鼠TLR 4（mTLR 4）。I型干扰素（IFN）信号转导是机体抵抗病毒和细菌感染的重要途径，如嗜肺军团菌，与嗜肺军团菌密切相关。伯内特氏菌我们最近发现，与其促进对C的保护，I型IFN信号促进由C.伯内特氏菌该建议的目的是研究hTLR 4表达小鼠的易感性增强与I型IFN信号传导之间的潜在联系。将检验以下假设：I型IFN促进C。在表达人TLR 4的小鼠中的贝氏体发病机制。具体目的1）确定I型IFN信号在C.在hTLR 4/MD 2小鼠中的贝氏体。2）确定I型IFN信号传导在hTLR 4/MD 2小鼠中产生容许性和限制性巨噬细胞亚群中的作用。在这个项目的结论，我们将有特点的先天免疫途径，有潜力开发新的治疗方法用于Q热。由于新的hTLR 4/MD 2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.