Role of IL-6 in the Pathogenesis of Yersinia enterocolitica infection

描述（由申请人提供）：食源性和水源性传染病是世界范围内发病率和死亡率的重要来源。儿童特别容易受到这些感染。虽然通常认为这只是世界发展中地区的问题，但胃肠道细菌感染仍然是美国严重的疾病来源。我们的长期目标是了解肠道中对小肠结肠炎耶尔森氏菌的宿主反应和宿主病原体相互作用，从而导致感染或病理的解决。Y.小肠结肠炎是我们研究中使用的极好病原体，因为它已作为细菌感染性疾病的范例之一。在这个建议中，我们扩大了我们的研究，看看IL-6在Y.小肠结肠炎我们推测IL-6可能是一个重要的调节炎症反应的感染，通过影响宿主细胞的细胞因子反应参与响应Y。小肠结肠炎我们还假设IL-6介导的炎症反应的缓和可能是由Y。小肠结肠炎病毒编码的分子。为了验证这些假设，我们提出了以下具体目标：1）鉴定响应于Y.小肠结肠炎感染和2）在感染期间在派伊尔集合淋巴结、肠系膜淋巴结和脾脏中响应IL-6的细胞。这些数据将使我们了解哪些宿主细胞正在调节宿主对感染的反应。3)检测IL-6调节的细胞因子在肠道耶尔森氏菌病免疫发病机制中的作用。缺乏IL-6的小鼠具有不同的细胞因子表达谱，并且这些细胞因子中的许多对疾病的解决至关重要，但是这些细胞因子的错误调节如何导致病理学尚不清楚。这些数据将探索IL-6介导的免疫应答调节与耶尔森氏菌毒力之间的联系。总之，这些数据将使我们深入了解IL-6如何有助于耶尔森氏菌感染的发病机制，以及如何在自限性感染期间预防免疫病理。这些数据可以提供深入了解慢性肠道炎症的病因。

DESCRIPTION (provided by applicant): Food and water borne infectious diseases are a significant source of morbidity and mortality world-wide. Children are especially at risk from these infections. Although often assumed to be only a problem in developing areas of the world, bacterial infections of the gastro-intestinal tract remain a serious source of disease in the US. Our long-term goal is to understand both host-response and host pathogen interactions in the gut to Yersinia enterocolitica that lead to resolution of infection or to pathology. Y. enterocolitica is an excellent pathogen to use in our studies as it has served as one of the paradigms of bacterial infectious diseases. In this proposal we expand our studies to look at the role of IL-6 in the modulation of the host response during Y. enterocolitica infection. We hypothesize that IL-6 may be a crucial regulator of inflammatory responses to infection by influencing the cytokine response of host cells involved in response to Y. enterocolitica infection. We also hypothesize that the IL-6 mediated tempering of inflammatory responses may be triggered by Y. enterocolitica encoded molecules. To test these hypotheses we propose the following specific aims: 1) Identify the cells producing IL-6 in response to Y. enterocolitica infection and 2) the cells responding to IL-6 during infection in the Peyer's patch, mesenteric lymph node, and spleen. These data will give us insight into which host cells are modulating the host response to infection. 3) Test the contribution of the IL-6 modulated cytokines to the immunopathogenesis of intestinal yersiniosis. Mice deficient in IL-6 have distinct cytokine expression profiles and many of these cytokines are critical to the resolution of disease but it is unknown how mis-regulation of these cytokines contributes to pathology. These data will explore the connection between IL-6 mediated modulation of the immune response and Yersinia virulence. Altogether, these data will give us insight into how IL-6 contributes to the pathogenesis of Yersinia infection and how immune pathologies are prevented during self limiting infections. These data may provide insight into the etiology of chronic intestinal inflammation.