BODY TEMPERATURE AND REGULATING HOST DEFENSES

发烧是对感染最初反应的一个关键因素。一般来说，发烧与感染期间存活率的提高有关，但其保护作用的机制在很大程度上尚不清楚。我们假设，在发热性疾病期间发生的核心温度上升对于宿主防御的最佳协调是必不可少的。我们的总体研究目标是确定发热期间核心温度升高影响发病率的机制，并表明核心温度升高到发烧水平会增强对细菌内毒素(LPS)的早期细胞因子反应，细菌内毒素是一种非复制激动剂。我们已经利用幼鼠(8-10周大)的部分放热性质开发了一种方法，在感染期间被动地将核心温度保持在发烧(39-40摄氏度)或无发烧(36.5-37.5摄氏度)水平。我们将使用这个模型来直接确定感染肺炎克雷伯氏菌的小鼠的核心温度变化的潜在影响：(1)确定核心温度升高是否增强了对肺炎克雷伯菌腹膜炎的遏制和减少其扩散；(2)确定将核心温度升高到发热水平是否会增强肺炎克雷伯菌腹膜炎期间侧支组织的损伤；(3)评估TNFpha表达变化或组织对TNFpha的反应性变化的潜在作用；以及(4)确定核心温度升高到发热水平是否对于肺炎克雷伯菌的宿主反应和生存进行最佳协调是必需的。拟议的研究结果将提供关于核心温度变化调节宿主防御机制的重要信息。由于有技术可以改变体温，拟议中的实验结果可以迅速转化为临床领域。了解核心温度在调节宿主防御中的作用可能会导致在感染期间管理体温的新方案，并可能确定治疗和预防感染性休克的新方法。

Fever is a key element of the initial response to infection. In general, fever is associated with improved survival during infections, but the mechanisms of its protective effects are largely unknown. We hypothesize that the increase in core temperatures that occurs during febrile illnesses is essential for optimal orchestration of the host defenses. Our overall research objective is to determine the mechanisms through which increases in core temperature during fever influence morbidity and showed that increases in core temperature to febrile levels enhances the early cytokine responses to bacterial endotoxin (LPS), a non-replicating agonist. We have taken advantage of the partial ectothermic nature of young (8-10 week old) mice to develop a method to passively maintain core temperatures at febrile (39-40 degrees Celsius) or afebrile (36.5- 37.5 degrees Celsius) levels during infections. We will use this model to directly determine the following potential effects of core temperatures changes in mice infected with Klebsiella pneumoniae, a clinically relevant and virulent bacterial pathogen: (1) determine if febrile core temperatures enhance containment and reduce dissemination of K. pneumoniae peritonitis; (2) determine if increasing core temperature to febrile levels enhances collateral tissue injury during K. pneumoniae peritonitis; (3) evaluate the potential roles of altered TNFalpha expression or tissue responsiveness to TNFalpha; and (4) determine if an increase in core temperature in core temperature to febrile levels is required for optimal orchestration of the host response and survival in K. pneumoniae pneumonia. The results of the proposed research will provide important information about the mechanisms through which changes in core temperature regulate host defenses. Because technology is available to modify body temperature, the results of the proposed experiments can be rapidly translated to the clinical area. Understanding the role of core temperature in regulating host defenses may lead to new protocols for managing body temperature during infections and may identify novel modalities for treating and preventing septic shock.