Hemostatic Factors as Determinants of Bacterial Virulence and Host Defense

止血因素是细菌毒力和宿主防御的决定因素

• 批准号: 7650126
• 负责人: JAY L DEGEN
• 金额: $ 36.41万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650126
• 关键词: Acute; Bacteremia; Binding; Blood Coagulation Factor; Blood Platelets; Cell Surface Proteins; Cells; Cessation of life; Coagulase; Coagulation Process; Communicable Diseases; Complex; Cues; Cutaneous; Deposition; Engineering; Event; Fibrin; Fibrinogen; Fibrinogen Receptors; Gene Targeting; Genetic; Goals; Greater sac of peritoneum; Hemostatic Agents; Host Defense; Human; Immune; Immune response; Immunologic Surveillance; Infection; Inflammatory; Inflammatory Response; Integration Host Factors; Integrins; Leukocyte Trafficking; Leukocytes; Life; Lymphatic; Mediating; Mus; Mutation; Natural Immunity; Pathogenesis; Peritonitis; Pharmacia brand of estropipate; Plasmin; Plasminogen; Plasminogen Activator; Process; Production; Protein C; Prothrombin; Research; Research Personnel; Role; Secretory Cell; Sepsis; Site; Staphylococcus aureus; Staphylococcus aureus auR protein; System; Testing; Therapeutic; Tissues; Virulence; antimicrobial; cytokine; design; extracellular; factor A; in vivo; leukocyte activation; macrophage; microbial; mutant; neutrophil; novel therapeutic intervention; pathogen; programs; prothrombin activator; receptor; response

DESCRIPTION (provided by applicant): The long-term objective of this research program is to understand the roles of key coagulation and fibrinolytic factors in inflammatory host defense and bacterial virulence. Since a rigorous understanding of these complex processes can only be achieved in an in vivo experimental setting, our proposed studies focus on innate immune surveillance and bacterial pathogenesis in gene-targeted mice with specific alterations in core hemostatic factors. The aims of this project center on the following specific hypotheses: i) host factors mediating fibrin deposition and dissolution are important determinants of the inflammatory response in vivo, ii) bacterial factors known to bind/activate host prothrombin, fibrinogen and plasminogen serve to subvert host defense, iii) leukocyte engagement of fibrin within challenged tissues is an important cue in "target recognition" leading to the implementation of effective antimicrobial functions, and iv) hemostatic factors control leukocyte activation events as well as macrophage egress from inflammatory sites into lymphatics. These hypotheses will be tested through detailed studies of S. aureus virulence/host defense in mice lacking fibrin(ogen) or expressing mutant forms of fibrinogen that either lack the leukocyte integrin receptor alphaMbeta2 binding motif, lack platelet integrin receptor alpha(IIb)beta3 binding motif, or cannot be converted to a fibrin matrix (Aim I). Further, the role of procoagulant and fibrinolytic factors in establishing S. aureus virulence/host defense will be determined through investigator-imposed genetic changes in prothrombin, plasminogen and their respective microbial-derived activators: coagulase and staphylokinase (Aim 2 and 3). Finally, the mechanistic role of neutrophils and macrophages in the fibrinogen/prothrombin-dependent bacterial clearance will be established in the context of S. aureus peritonitis (Aim 3). The proposed studies will provide a detailed understanding of the cross-talk between the hemostatic and inflammatory systems in the implementation of effective antimicrobial response in vivo. Further, these studies may illuminate therapeutic strategies centering on specific hemostatic system components that are effective in the treatment of life-threatening microbial infection/sepsis. Lay Description: The bacterial species that are the most common causes of human suffering and death have uniformly evolved the means to engage coagulation factors, apparently as a means of subverting host defense. The goal of this research is to develop a detailed mechanistic understanding of the role of host hemostatic factors in bacterial virulence and the inflammatory response as a step toward novel therapeutic interventions for life-threatening infectious disease.

描述（由申请人提供）：本研究项目的长期目标是了解关键凝血和纤溶因子在炎症宿主防御和细菌毒力中的作用。由于对这些复杂过程的严格理解只能在体内实验环境中实现，因此我们提出的研究重点是先天性免疫监测和核心止血因子特异性改变的基因靶向小鼠的细菌发病机制。本项目的目标围绕以下具体假设：1)介导纤维蛋白沉积和溶解的宿主因子是体内炎症反应的重要决定因素，2)已知结合/激活宿主凝血酶原、纤维蛋白原和纤溶酶原的细菌因子有助于破坏宿主防御，3)受损组织内纤维蛋白的白细胞参与是“目标识别”的重要线索，从而实现有效的抗菌功能。iv)止血因子控制白细胞活化事件以及巨噬细胞从炎症部位进入淋巴。这些假设将通过在缺乏纤维蛋白（原）或表达纤维蛋白原突变形式的小鼠中进行的金黄色葡萄球菌毒力/宿主防御的详细研究来验证，这些突变形式要么缺乏白细胞整合素受体α β 2结合基序，要么缺乏血小板整合素受体α (IIb) β 3结合基序，要么不能转化为纤维蛋白基质（Aim I）。此外，促凝剂和纤溶因子在建立金黄色葡萄球菌毒力/宿主防御中的作用将通过研究者施加的凝血酶原、纤溶酶原及其各自的微生物衍生激活剂：凝固酶和葡萄激酶的遗传变化来确定（目的2和3）。最后，中性粒细胞和巨噬细胞在纤维蛋白原/凝血酶原依赖性细菌清除中的机制作用将在金黄色葡萄球菌腹膜炎的背景下确定（目的3）。拟议的研究将提供一个详细的了解止血和炎症系统之间的串扰在体内实施有效的抗菌反应。此外，这些研究可能阐明以特定止血系统成分为中心的治疗策略，这些成分可有效治疗危及生命的微生物感染/败血症。概要描述：导致人类痛苦和死亡的最常见的细菌物种都进化出了参与凝血因子的手段，显然是一种破坏宿主防御的手段。本研究的目的是对宿主止血因子在细菌毒力和炎症反应中的作用进行详细的机制理解，作为对危及生命的传染病进行新型治疗干预的一步。