Pathogen-induced immune and stress responses mediated by bZIP transcription factors

项目说明 中毒组链球菌是普遍存在的微生物，在人类口咽中定居。在易感人群中 这些微生物是重要的机会性病原体，它们已被证明能引起广泛的 人类的感染性并发症，包括菌血症、眼眶蜂窝织炎、感染性关节炎和感染性 心内膜炎。然而，尽管这些感染具有临床意义，但其发病机制 人们对其病理生理学知之甚少。这些微生物产生的过氧化氢(过氧化氢) 已被确定为一个重要的毒力因素。此外，这一组成员产生的过氧化氢 如口腔链球菌和中型链球菌可诱导上皮细胞和巨噬细胞死亡，而过氧化氢 肺炎链球菌产生对细胞应激通路的激活有深远的影响 肺上皮细胞。基因易驯化的模式生物秀丽线虫提供了一个机会 描述整个生物体的病理生理学特征，并阐明非免疫细胞如何 促进先天免疫和压力反应。在这项研究中，我们建议阐明激活的机制 病原体诱导的免疫和应激反应的米蒂斯组链球菌。我们的中心假设是 免疫和氧化应激反应是由bZIP转录因子ZIP-2和ZIP-10通过 病原体衍生的过氧化氢。为了解决我们的假设，将测试以下目标；具体目标#1。到 阐明bZIP转录因子ZIP-2介导效应器触发免疫的机制 线虫对链球菌衍生的过氧化氢的反应。具体目标2.我们将确定机制 通过bZIP转录因子ZIP-10激活免疫和氧化应激反应 病原体在蠕虫中产生的过氧化氢。具体目标#3.证明保护这些 在人类牙龈成纤维细胞中识别的AIMS 1和AIMS 2机制。这项拟议的研究意义重大，因为 我们将确定由米蒂斯组链球菌产生的过氧化氢如何导致病原体相关的破坏 细胞过程，进而激活保护机制。阐明保护机制 将有助于确定对抗这些病原体的新治疗策略。

Project Description The mitis group streptococci are ubiquitous microorganisms that colonize the human oropharynx. In susceptible hosts, these organisms are important opportunistic pathogens and they have shown to cause a wide range of infectious complications in humans, which includes bacteremia, orbital cellulitis, septic arthritis, and infective endocarditis. However, despite the clinical significances of these infections, the mechanisms of pathogenesis and the pathophysiology are poorly understood. Hydrogen peroxide (H2O2) produced by these microorganisms has been identified as an important virulence factor. Furthermore, H2O2 produced by members of this group such as Streptococcus oralis and Streptococcus mitis induced epithelial cell and macrophage death, while H2O2 produced by Streptococcus pneumoniae had a profound effect on the activation of cellular stress pathways in lung epithelial cells. The genetically tractable model organism Caenorhabditis elegans provides an opportunity to characterize the pathophysiology in context of the whole organism and to elucidate how non-immune cells facilitate innate immune and stress responses. In this study, we propose to elucidate mechanisms of activation of pathogen-induced immune and stress responses by the mitis group streptococci. Our central hypothesis is that immune and oxidative stress responses are mediated by the bZIP transcription factors ZIP-2 and ZIP-10 via pathogen-derived H2O2. To address our hypothesis the following aims will be tested; Specific Aim #1. To elucidate the mechanism how the bZIP transcription factor, ZIP-2 mediates the effector-triggered immune response in C. elegans against streptococcal-derived H2O2. Specific Aim #2. We will determine the mechanisms of activation of an immune and oxidative stress response via the bZIP transcription factor ZIP-10 in response to the pathogen-derived H2O2 in the worm. Specific Aim #3. To demonstrate the conservation of these mechanisms identified in aims 1 and 2 in human gingival fibroblasts. The proposed study is significant because we will identify how H2O2 produced by the mitis group streptococci causes pathogen-associated disruption of cellular processes and in turn the activation of protective mechanisms. Elucidating the protective mechanisms will help identify novel therapeutic strategies to combat these pathogens.