Role of Toll-like receptors in Coxiella burnetii infection

描述（由申请人提供）：即使C。自20世纪30年代以来，贝氏体已被公认为Q热因子，但我们对宿主细胞进入、疾病发病机制或该因子如何避免免疫清除仍有不完全的了解。Toll样受体（TLR）途径已被假设在细菌的摄取和清除中发挥作用，但我们对Q热中TLR的理解是不完整的。虽然对C.尽管已经公开了TLR缺陷动物中腹膜的贝氏体感染，但迄今为止还没有使用TLR缺陷动物和通过肺的自然感染途径的报道。肺部TLR的使用是独特的，因此需要这些研究来获得TLR在C.贝氏体感染在初步研究中，我们已经检测到肺攻击后TLR 2、TLR 4和MyD 88（TLRs 2和4的关键炎症信号传导分子）缺陷动物中细菌清除的差异，其中一些（差异）与腹膜感染后其他人定义的差异相反。我们建议扩大和确认这些初步意见。我们对TLR在C.贝氏体感染的关键在于TLR功能是否与骨髓来源的巨噬细胞最相关，或者非巨噬细胞或甚至非骨髓来源的细胞上的TLR是否显著有助于宿主对细菌的应答。特别令人感兴趣的是肥大细胞TLR识别/功能在C.贝氏菌致病机理这些问题也将在拟议的研究中加以探讨。最后，拟议研究的创新组成部分将涉及使用新的人TLR 4/MD 2转基因小鼠来比较人和小鼠TLR 4对C. Burnetii in vivo.在该提议中要测试的具体假设是：TLR信号传导在宿主/C中是重要的。肺内的贝氏交互作用。这一假设将在以下具体目标中加以阐述。目标1：比较C。在肺攻击后野生型和TLR-和MyD 88缺陷型小鼠中的贝氏体感染。目的2：确定TLR在造血和非造血细胞反应中的重要性，包括肥大细胞在C。肺部伯氏体感染目标3：比较 C.在人TLR 4/MD 2转基因小鼠和小鼠TLR 4感受态小鼠中的贝氏体感染应答。 公共卫生相关性：目前，Q热的唯一治疗方法是使用抗生素，必须在感染后尽早开始使用，并延长使用时间才能有效。因此，需要开发用于对抗Q热的新疗法。来自这些基础科学研究的信息应该有助于开发未来的疫苗和/或佐剂来对抗Q热。

DESCRIPTION (provided by applicant): Even though C. burnetii has been recognized as the Q fever agent since the 1930s, we still have an incomplete understanding of host cell entry, disease pathogenesis or how the agent avoids immune clearance. Toll-like receptor (TLR) pathways have been hypothesized to play a role in bacterial uptake and clearance, but our understanding of TLRs in Q-fever is incomplete. Though a few studies of C. burnetii infection of the peritoneum in TLR deficient animals have been published, to date there have been no reports using TLR deficient animals and the natural route of infection via the lung. Lung TLR usage is unique, thus these studies are required to gain a truly relevant picture of the role of TLRs in C. burnetii infection. In preliminary studies we have detected differences in bacterial clearance in TLR2, TLR4 and MyD88 (Key inflammatory signaling molecule for TLRs 2&4) deficient animals following pulmonary challenge, some of which (differences) are contrary to what others have defined following peritoneal infection. We propose to expand on and confirm these preliminary observations. Another deficiency in our understanding of the role of TLRs in C. burnetii infection is whether TLR function is most relevant to bone-marrow derived macrophages, or whether TLRs on non-macrophages or even non-bone-marrow derived cells significantly contribute to host responses against the bacterium. Of particular interest is the potential role of TLR recogntion/function by mast cells in C. burnetii pathogenesis. These issues will also be examined in the proposed studies. Finally, an innovative component of the proposed studies will involve use of novel, human TLR4/MD2 transgenic mice to compare human and mouse TLR4 responses to C. burnetii in vivo. The specific hypothesis to be tested in this proposal is: TLR signaling is important in the host/C. burnetii interaction in the lung. This hypothesis will be addressed in the following Specific Aims. Aim 1: Compare C. burnetii infection in wild type, and TLR- and MyD88 deficient mice following lung challenge. Aim 2: Determine the importance of TLRs on the responses of hematopoietic and non-hematopoietic cells, including the role of mast cells following C. burnetii infection in the lung. Aim 3: Compare C. burnetii infection response in human TLR4/MD2 transgenic and mouse TLR4 competent mice. PUBLIC HEALTH RELEVANCE: Currently, the only treatment for Q-fever is the use of antibiotics, which must be started as early as possible after infection and used for extended periods of time in order to be effective. As such, there is a need for the development of new therapeutics for use against Q-fever. Information from these basic science studies should facilitate development of future vaccines and/or adjuvants to counter Q-fever.