Role of Toll-like receptors in Coxiella burnetii infection

描述（由申请人提供）：尽管自20世纪30年代以来，伯纳蒂胞杆菌已被认为是Q热病原体，但我们对宿主细胞进入、疾病发病机制或病原体如何避免免疫清除仍有不完全的了解。toll样受体（TLR）途径被假设在细菌摄取和清除中发挥作用，但我们对q热中TLR的理解尚不完整。虽然已经发表了一些关于TLR缺陷动物腹膜伯氏梭菌感染的研究，但迄今为止还没有使用TLR缺陷动物和通过肺部自然途径感染的报道。肺部TLR的使用是独特的，因此需要这些研究来获得TLR在伯氏梭菌感染中真正相关的作用。在初步研究中，我们已经检测到TLR2、TLR4和MyD88 （TLR2和4的关键炎症信号分子）缺陷动物在肺部感染后细菌清除率的差异，其中一些差异与其他腹膜感染后的定义相反。我们建议扩大和证实这些初步观察结果。我们对TLR在伯氏杆菌感染中的作用的理解的另一个不足是TLR功能是否与骨髓源性巨噬细胞最相关，或者TLR作用于非巨噬细胞甚至非骨髓源性细胞是否显著促进宿主对细菌的反应。特别令人感兴趣的是肥大细胞TLR识别/功能在伯氏杆菌发病机制中的潜在作用。这些问题也将在拟议的研究中加以审查。最后，拟议研究的一个创新部分将涉及使用新型的人类TLR4/MD2转基因小鼠来比较人类和小鼠TLR4对伯氏梭菌的体内反应。本提案要检验的具体假设是：TLR信号在host/C中很重要。伯纳蒂菌在肺部的相互作用。这一假设将在以下具体目标中得到解决。目的1：比较野生型和TLR-和MyD88缺陷小鼠在肺部攻击后的伯纳蒂胞杆菌感染。目的2：确定TLRs对造血细胞和非造血细胞反应的重要性，包括肺伯氏杆菌感染后肥大细胞的作用。目标3：比较

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.