Defenses against Acute Chronic Infection with C pneumoniae

寄主感知病原生物入侵并对控制作出适当反应的能力 感染是生存的首要条件。然而，在某些情况下，夸大的炎症反应可能导致旁观者受伤和全身炎症症状，可能导致与压倒性感染相关的发病率和死亡率。促炎症细胞因子白介素1是宿主抵抗多种感染状态的重要介质。例如，IL-1是在气管内注射脂多糖后在肺内产生的，它的存在与肺炎的肺部炎症和细菌负荷直接相关。IL-1是控制多种细胞内病原体所必需的，如李斯特氏菌、利什曼原虫和结核分枝杆菌。然而，对IL-1在控制肺炎衣原体中的作用知之甚少，肺炎衣原体是一种专性的细胞内细菌，与 肺炎衣原体具有多种急性感染过程，如非典型肺炎、支气管炎和咽炎；肺炎衣原体的慢性感染也与各种慢性炎症状态有关，包括动脉粥样硬化。 这一提议的中心假设是肺炎链球菌诱导的IL-1 5 在防御急性和慢性感染中的相互矛盾的角色。我们的初步数据显示 与其他相关衣原体不同，肺炎衣原体具有直接诱导小鼠骨髓来源的巨噬细胞分泌IL-1 ft的独特能力，并且这种诱导依赖于NALP3/ASC炎症体复合体。我们认为，尽管IL-1(3)在急性肺炎的消退中起着重要作用，但在慢性感染的背景下，它的诱导导致了以动脉粥样硬化斑块形成为特征的炎症。 为了进一步了解C.PNET/MON/AE诱导的IL-IP在疾病发展中的作用，我们 提出以下具体目标：(1)明确肺炎衣原体感染的巨噬细胞诱导IL-1β产生的分子机制；(2)研究IL-IP和IL-1受体在急性细菌性肺炎和全身炎症反应中的作用；(3)研究IL-IP和IL-1受体在以动脉粥样硬化为特征的慢性炎症斑块形成中的作用。

The ability of a host to sense invasion by pathogenic organisms and respond appropriately to control infection is paramount to survival. In some cases, however, an exaggerated inflammatory response can lead to bystander injury and systemic inflammatory symptoms, possibly contributing to the morbidity and mortality associated with overwhelming infections. The pro-inflammatory cytokine interleukin (IL)-1 is a critical mediator of host defense against a variety of infectious states. For example, IL-1 is produced in the lung after intratracheal administration of lipopolysaccharide, and its presence is directly associated with lung inflammation and bacterial burden in pneumonia. IL-1 is required for control of a variety of intracellular pathogens, such as Listeria, Leishmania, and Mycobacterium tuberculosis. However, little is known about the role of IL-1 in control of Chlamydophila pneumoniae, an obligate intracellular bacteria that is associated with a variety of acute infectious processes, sush as atypical pneumonia, bronchitis, and pharyngitis; chronic infection with C. pneumoniae has also been linked to a variety of chronic inflammatory states, including atherosclerosis. The central hypothesis of this proposal is that C. pneumoniae-induced IL-1 fiplays contradictory roles in the defense of acute vs. chronic infections. Our preliminary data demonstrates that C. pneumoniae, unlike other related chlamydia species, has the unique ability to directly induce IL-1 ft secretion from murine bone marrow derived macrophages, and that this induction is dependent on the NALP3/ASC inflammasome complex. We believe that while IL-1 (3 plays an important role in resolution of acute pneumonia, its induction in the setting of chronic infection contributes to the inflammation that is characteristic of atherosclerotic plaque formation. To further understand the role of C. pnet/mon/ae-induced IL-ip in the development of disease, we propose the following Specific Aims: (1) To define the molecular mechanism behind the induction of IL-1 p by macrophages infected with C. pneumoniae; (2) To examine the role IL-ip and the IL-1 receptor in acute bacterial pneumonia and the systemic inflammatory response; and (3) To examine the role IL-ip and the IL-1 receptor in the chronic inflammatory plaque formation that is characteristic of atherosclerosis.