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

描述(申请人提供)：食物和水传播的传染病是世界范围内发病率和死亡率的重要来源。儿童尤其容易受到这些感染。尽管通常被认为只是世界发展中地区的一个问题，但在美国，胃肠道细菌感染仍然是一个严重的疾病来源。我们的长期目标是了解肠道中宿主反应和宿主病原体的相互作用，从而导致感染的解决或病理。小肠结肠炎耶尔森氏菌是一种很好的病原体，在我们的研究中使用，因为它已经成为细菌感染性疾病的范例之一。在这项提案中，我们扩展了我们的研究，以观察IL-6在小肠结肠炎耶尔森菌感染过程中对宿主反应的调节作用。我们推测，IL-6可能通过影响宿主细胞对小肠结肠炎耶尔森菌感染的细胞因子反应而成为感染炎症反应的重要调节因子。我们还假设，IL-6介导的炎症反应的缓和可能是由小肠结肠炎耶尔森菌编码的分子触发的。为了验证这些假说，我们提出了以下具体目标：1)确定在小肠结肠炎耶尔氏菌感染时产生IL-6的细胞，以及2)在Peyer氏斑、肠系膜淋巴结和脾中感染时对IL-6做出反应的细胞。这些数据将使我们深入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病免疫发病机制中的作用。IL-6缺乏的小鼠有不同的细胞因子表达谱，其中许多细胞因子对疾病的解决至关重要，但这些细胞因子的错误调节如何导致病理尚不清楚。这些数据将探索IL-6介导的免疫反应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如何在耶尔森菌感染的发病机制中发挥作用，以及如何在自限性感染期间预防免疫病理。这些数据可能为慢性肠炎的病因提供洞察力。

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.