Modulation of the innate immunity by bacterial signaling molecules

细菌信号分子调节先天免疫

• 批准号: 7510589
• 负责人: Vladimir V Kravchenko
• 金额: $ 23.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7510589
• 关键词: Accounting; Acetylmuramyl-Alanyl-Isoglutamine; Address; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Appendix; Applications Grants; Bacteria; Bacterial DNA; Bacterial Infections; Biochemical Genetics; Biological; Biological Assay; Cell Death; Cells; Cellular Stress; Chemicals; Chronic; Class; Collaborations; Cystic Fibrosis; DPYD gene; Data; Dental caries; Dihydropyrimidine Dehydrogenase; Disease; Environment; Evaluation; Family; Family member; Growth; Host Defense Mechanism; Immune; Immune System Diseases; Immune response; Immune system; Immunity; In Vitro; Infection; Inflammatory; Injury; Investigation; Knowledge; Laboratories; Lead; Lipopolysaccharides; Mammalian Cell; Measurement; Mediator of activation protein; Messenger RNA; Microbe; Microbial Biofilms; Mitogen-Activated Protein Kinases; Molecular; Mouth Diseases; Myelogenous; Myeloid Cells; N-(3-oxododecanoyl)homoserine lactone; Natural Immunity; Oligonucleotides; Oligopeptides; Oral; Oral cavity; Organ; Organism; Pathway interactions; Peptides; Peptidoglycan; Personal Satisfaction; Phase; Phosphorylation; Polysaccharides; Porphyromonas gingivalis; Proteins; Public Health; Publications; Publishing; Research; Research Institute; Ribose; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Surface; TLR4 gene; Tissues; Toll-like receptors; Tooth structure; Virulence Factors; Work; antimicrobial; base; cell growth; cell type; chemical synthesis; chemokine; computerized data processing; cytokine; design; homoserine lactone; immune function; in vivo; man; member; microbial; novel therapeutics; pulmonary function; quorum sensing; receptor; research study; response; soft tissue

DESCRIPTION (provided by applicant): We propose to investigate the effects of key molecules used by microbes to coordinate biofilm formation, namely bacterial quorum sensing (QS) factors, on cells of the host innate immune system. Biofilms are clinically important, accounting for over 80 percent of microbial infections in the body. The importance of bacterial QS factors in biofilm formation is supported by a large body of in vitro and in vivo data resulting from genetic, biochemical and biological studies with Gram-negative and Gram-positive organisms. QS factors are small, diffusible molecules of different chemical classes that include the AHL series, oligopeptides, and the ribose-derived DPD/AI-2 molecule. The presence of QS factors in biofilms is well documented. In addition, biofilms release a multiplicity of other biologically active, bacterially-derived molecules, such as bacterial lipopolysaccharides (LPS), peptidoglycan fragments, and bacterial DNA, into the local environment. These bacterial products stimulate the host innate immune response via receptors that include those of the Toll-like receptor (TLR) and the Nod-like receptor (NLR) families. Yet despite the presence of normal systemic immune function, biofilms still form. This paradox may be due to bacterial factors that lead to a local suppression of normal innate immune mechanisms. Thus, we hypothesize that in the micro-environment where biofilms form, one or more classes of QS factors may contribute to immune dysfunction through direct or indirect effects on host cells. Based on our recently published data, we postulate that some QS factors are "anti-inflammatory" in their actions on host cells; however, other QS factors might act in a pro-inflammatory manner. The experiments outlined here will evaluate which members of the QS factor classes have the ability to modulate normal host innate immune responses, to understand the underlying molecular mechanisms of this modulation and will, ultimately, provide information needed to develop new therapeutic strategies. This application brings together two highly regarded research groups located at The Scripps Research Institute - the Ulevitch group with many years of expertise in studies of fundamental mechanisms of innate immunity and the Janda laboratory that is internationally recognized for its work on the chemical synthesis of QS factors. We believe this collaboration will bridge a major gap in our understanding about how bacterial signaling processes might also modulate general host responses and host immunity in particular. PUBLIC HEALTH RELVANCE Biofilm formation in man is present in a majority of disease states where chronic bacterial infection leads to tissue destruction and loss of organ function. This includes diseases as diverse as dental caries and loss of pulmonary function in cystic fibrosis. This proposal is designed to bridge the gap in our knowledge about bacterial-derived biofilms influence the host immune response in the micro-environment where infections occur. The specific focus is on bacterial quorum sensing factors that are essential signals for biofilm formation by the microbe and that we have recently shown have profound effects on host immunity. By further identifying the underlying mechanisms whereby quorum sensing factors may influence host immunity we expect to design new therapeutic approaches to treating chronic infection in man.

描述（由申请人提供）：我们建议研究微生物用来协调生物膜形成的关键分子，即细菌群体感应（QS）因子，对宿主先天免疫系统细胞的影响。生物膜在临床上很重要，占体内微生物感染的 80% 以上。细菌 QS 因子在生物膜形成中的重要性得到了大量体外和体内数据的支持，这些数据来自对革兰氏阴性和革兰氏阳性生物体的遗传、生化和生物学研究。 QS 因子是不同化学类别的可扩散小分子，包括 AHL 系列、寡肽和核糖衍生的 DPD/AI-2 分子。生物膜中 QS 因子的存在已有充分记录。此外，生物膜还会向局部环境释放多种其他具有生物活性的细菌衍生分子，例如细菌脂多糖 (LPS)、肽聚糖片段和细菌 DNA。这些细菌产物通过受体（包括 Toll 样受体 (TLR) 和 Nod 样受体 (NLR) 家族）刺激宿主先天免疫反应。然而，尽管存在正常的全身免疫功能，生物膜仍然形成。这种悖论可能是由于细菌因素导致正常先天免疫机制的局部抑制。因此，我们假设在生物膜形成的微环境中，一类或多类 QS 因子可能通过对宿主细胞的直接或间接影响而导致免疫功能障碍。根据我们最近发表的数据，我们假设一些 QS 因子对宿主细胞具有“抗炎”作用；然而，其他 QS 因素可能会以促炎的方式发挥作用。这里概述的实验将评估 QS 因子类别的哪些成员具有调节正常宿主先天免疫反应的能力，以了解这种调节的潜在分子机制，并最终提供开发新治疗策略所需的信息。该应用汇集了位于斯克里普斯研究所的两个备受推崇的研究小组——在先天免疫基本机制研究方面拥有多年专业知识的 Ulevitch 小组和因其在 QS 因子化学合成方面的工作而获得国际认可的 Janda 实验室。我们相信，这次合作将弥补我们对细菌信号传导过程如何调节一般宿主反应，特别是宿主免疫的理解上的重大差距。公共卫生相关性 人类生物膜形成存在于大多数疾病状态中，其中慢性细菌感染导致组织破坏和器官功能丧失。这包括龋齿和囊性纤维化导致的肺功能丧失等多种疾病。该提案旨在弥补我们关于细菌源性生物膜影响感染发生的微环境中宿主免疫反应的知识空白。特别关注的是细菌群体感应因子，它们是微生物形成生物膜的重要信号，并且我们最近证明它对宿主免疫具有深远的影响。通过进一步确定群体感应因子可能影响宿主免疫的潜在机制，我们期望设计新的治疗方法来治疗人类慢性感染。