BODY TEMPERATURE AND REGULATING HOST DEFENSES

发烧是感染初期反应的一个关键因素。一般来说，发烧与感染期间生存率的提高有关，但其保护作用的机制在很大程度上是未知的。我们假设，在发热性疾病期间发生的核心温度的升高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至发热水平可增强细胞因子对细菌内毒素（LPS）的早期反应，LPS是一种非复制激动剂。我们利用幼龄（8-10周龄）小鼠的部分异温性，开发了一种方法，在感染期间被动地将核心温度维持在发热（39-40摄氏度）或不发热（36.5- 37.5摄氏度）水平。我们将使用该模型直接确定核心温度变化对感染肺炎克雷伯菌（一种临床相关且毒性强的细菌病原体）的小鼠的以下潜在影响：(1)确定发热核心温度是否增强了肺炎克雷伯菌腹膜炎的遏制和减少传播；(2)确定将核心温度升高至发热水平是否会增加肺炎克雷伯菌腹膜炎的侧枝组织损伤；(3)评估TNFalpha表达改变或组织对TNFalpha的反应性的潜在作用；(4)确定在肺炎克雷伯菌肺炎中，是否需要将核心温度升高到发热水平以优化宿主反应和生存。本研究结果将为核心温度变化调控宿主防御机制提供重要信息。由于技术可以改变体温，因此所提出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模式。

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.