Development of a mouse model of peptidoglycan-induced pathology

肽聚糖诱导病理学小鼠模型的开发

基本信息

批准号：
8898008
负责人：
Kenneth Mark Coggeshall
金额：
$ 21.44万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898008
关键词：
A Mouse Address Animals Antibiotic Resistance Antibodies Applied Genetics Area Binding Biology Blood coagulation Cells Classical Complement Pathway Clinic Clinical Coagulation Process Communicable Diseases Complement Complement Receptor Cost Savings Development Disseminated Intravascular Coagulation Environment Event Exhibits Fc Receptor Functional disorder Future Gram-Positive Bacteria Health Human IgG Receptors Immune Immunoglobulin G In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Knock-out Laboratory mice Measures Methods Modeling Molecular Mus Papio Passive Immunization Pathology Pattern Peptidoglycan Phagocytosis Plasma Platelet Activation Primates Production Protocols documentation Receptor Cell Relative (related person)Reporting Role Sepsis Staging Sterility Supportive care Surface Surveys Testing Therapeutic Transgenic Mice Vaccinated Work base cytokine in vivo knockout gene macrophage model development monocyte mouse model neutrophil nonhuman primate pathogen receptor response

项目摘要

DESCRIPTION (provided by applicant): Peptidoglycan (PGN) is a highly-conserved pathogen-associated molecular pattern that is present in especially high amounts in Gram-positive bacteria. Humans and non-human primates respond to PGN in vitro by production of inflammatory cytokines and platelet activation and in vivo by systemic inflammation and disseminated intravascular coagulation (DIC). Paradoxically, mice and mouse cells show minimal responses to PGN. We recently discovered that both humans and non-human primates naturally express IgG antibodies that cross-react with PGN derived from a variety of pathogens, while mice lack these antibodies. The anti-PGN antibodies were essential for PGN responses, based on the following observations: 1. All surveyed healthy humans express anti-PGN antibodies that opsonize PGN. 2. PGN activates the classical complement pathway in human serum and plasma. 3. Intact but not F(ab')2 fragments of normal human IgG support PGN-triggered inflammatory cytokine production in human innate immune cells. 4. Expression of the human IgG receptor Fc?RIIa in HEK293 cells permitted the cells to bind and phagocytose PGN in a human IgG-dependent manner. 5. Baboons responded to an in vivo challenge of PGN with features of systemic inflammation and DIC; the response directly correlated with their individual titer of anti-PGN IgG antibodies. We hypothesize that the presence and level of anti-PGN IgG is associated with the pathology caused by PGN and thus of Gram-positive pathogens. This project will directly test whether the presence of the anti-PGN IgG in humans contributes to the pathogenic effects of PGN by passive transfer of human IgG containing anti-PGN antibodies to human Fc?RIIA-transgenic mice. We will also generate a mouse model for PGN-induced pathology by making mice immune to PGN, challenging immune or naive mice in vivo, and measuring signs of inflammation. A mouse model will be an important breakthrough as it will permit a better understanding of the response to the PGN pathogen-associated molecular pattern, shared by all Gram-positive pathogens.

描述（由申请人提供）：肽聚糖（PGN）是一种高度保存的病原体相关分子模式，在革兰氏阳性细菌中特别高。人类和非人类灵长类动物通过产生炎症细胞因子和血小板激活以及通过全身性炎症和传播血管内凝结（DIC）来对PGN的体外做出反应。矛盾的是，小鼠和小鼠细胞对PGN的反应最少。我们最近发现，人类和非人类灵长类动物都自然表达与来自多种病原体的PGN交叉反应的IgG抗体，而小鼠缺乏这些抗体。基于以下观察结果，抗PGN抗体对于PGN反应至关重要：1。所有接受调查的健康人都表现出对PGN进行调查的抗PGN抗体。 2。PGN激活人血清和血浆中的经典补体途径。 3。完整但不是F（ab'）2正常人IgG的片段支持PGN触发的人类先天免疫细胞的炎症细胞因子产生。 4。在HEK293细胞中人IgG受体Fc？riiA的表达允许细胞以人IgG依赖性方式结合和吞噬细胞PGN。 5。狒狒对PGN的体内挑战做出了反应，具有系统性炎症和DIC的特征。响应与它们的抗PGN IgG抗体的单个滴度直接相关。我们假设抗PGN IgG的存在和水平与PGN引起的病理以及革兰氏阳性病原体有关。该项目将直接测试人类中抗PGN IgG的存在是否通过被动转移含有抗PGN抗体对人Fc？riia-转基因小鼠的人IgG的被动转移来促进PGN的致病作用。我们还将通过使小鼠免疫对PGN，在体内挑战或幼稚小鼠，并测量炎症的迹象来生成用于PGN诱导的病理的小鼠模型。小鼠模型将是一个重要的突破，因为它将更好地理解所有革兰氏阳性病原体共享的对PGN病原体相关的分子模式的反应。