Engineering the immune response for improved resolution of Staphylococcus infecti

设计免疫反应以提高感染葡萄球菌的分辨率

• 批准号: 8701454
• 负责人: Scott Irwin Simon
• 金额: $ 37.09万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701454
• 关键词: Abscess; Animals; Antibiotic Resistance; Apoptosis; Autocrine Communication; Biopolymers; Blood Circulation; Bone Marrow; Bone Tissue; Cell Differentiation process; Chronic; Clinical; Connective Tissue; Cutaneous; Data; Detection; Drug Delivery Systems; Employee Strikes; Engineering; Feedback; Genus staphylococcus; Goals; Half-Life; Healed; Hematopoietic; Hematopoietic stem cells; Host Defense; Hydrogels; Immune; Immune response; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Laboratories; Lead; Leukocytes; Methodology; Microbial Biofilms; Muscle; Myelogenous; Normal tissue morphology; Nosocomial Infections; Paracrine Communication; Pathogen detection; Patients; Phenotype; Proliferating; Public Health; Publishing; Recruitment Activity; Resolution; Role; Signal Transduction; Site; Skin; Skin Tissue; Soft Tissue Infections; Solutions; Staphylococcus aureus; Stem cells; System; TLR2 gene; Therapeutic; Time; Tissue Engineering; Tissues; Transgenic Mice; Translating; Wound Healing; antimicrobial; bactericide; combat; defined contribution; fluorescence imaging; healing; immunoregulation; improved; in vivo; innovation; methicillin resistant Staphylococcus aureus; microbial; mouse model; neutrophil; pathogen; regenerative; resistant strain; response; stem; therapeutic target; tissue regeneration; trafficking; wound

DESCRIPTION (provided by applicant): Polymorphonuclear (PMN) leukocytes are critical in the innate immune response against pathogens. Staphylococcus aureus (SA) is among the most common nosocomial infections and the most frequent cause of non-healing skin wounds. PMN recruitment and abscess formation in cutaneous wounds is a hallmark of these infections and is required for bacterial clearance. However, the increasing emergence of biofilm forming antibiotic-resistant strains such as methicillin resistant SA (MRSA) has complicated their treatment and created a serious public health threat. For instance, MSRA involvement in skin and soft tissue infections increased from 4% to 42% between 2000 and 2005 and remains high. Published data from our laboratory indicates that strategic manipulation of the inflammatory response of PMN at the site of a cutaneous wound suppresses infection and improves the efficiency of non-scar healing. These studies employ non- invasive whole animal fluorescence imaging of transgenic mice expressing EGFP-PMN. This methodology provides a real-time multiparameter readout of the dynamic changes in PMN recruitment and lifetime, SA burden, and wound closure. We propose to investigate three distinct mechanisms that act in concert to recruit PMN for host defense in SA infected tissue, including: (1) a robust and sustained mobilization of PMN from the bone marrow, (2) a prolonged in vivo survival of PMN within the abscess, and (3) trafficking of ckit+ hematopoietic stem and progenitor cells (HSPC) that proliferate and differentiate into mature PMN within the wound. The central hypothesis governing this proposal is that PMN and HSPC recruitment and function in the abscess can be engineered to optimize clearance of microbial infections and prevent aberrant inflammation that delays normal tissue healing. A translational goal will be implementation of a hydrogel delivery system to guide the innate immune response for improving resolution of a persistent SA infection in a mouse model of tissue injury.

描述（由申请人提供）：多形核（PMN）白细胞在针对病原体的先天免疫反应中至关重要。金黄色葡萄球菌 (SA) 是最常见的医院感染之一，也是导致皮肤伤口不愈合的最常见原因。 皮肤伤口中 PMN 的募集和脓肿形成是这些感染的标志，也是细菌清除所必需的。然而，生物膜形成的抗生素耐药菌株（例如耐甲氧西林 SA (MRSA)）的不断出现，使其治疗变得复杂，并造成了严重的公共健康威胁。例如，2000 年至 2005 年间，MSRA 涉及皮肤和软组织感染的比例从 4% 增加到 42%，并且仍然很高。我们实验室公布的数据表明，对皮肤伤口处 PMN 的炎症反应进行策略性调控可以抑制感染并提高非疤痕愈合的效率。这些研究采用表达 EGFP-PMN 的转基因小鼠的非侵入性整体动物荧光成像。该方法提供了 PMN 募集和寿命、SA 负担和伤口闭合动态变化的实时多参数读数。我们建议研究三种不同的机制，这些机制协同作用，在 SA 感染的组织中招募 PMN 进行宿主防御，包括：(1) 从骨髓中强有力且持续地动员 PMN，(2) PMN 在脓肿内延长体内存活时间，(3) ckit+ 造血干细胞和祖细胞 (HSPC) 的运输，这些细胞在脓肿内增殖并分化为成熟的 PMN。 伤口。该提议的核心假设是，可以对脓肿中的 PMN 和 HSPC 募集和功能进行设计，以优化微生物感染的清除并防止延迟正常组织愈合的异常炎症。转化目标是实施水凝胶递送系统来指导先天免疫反应，从而提高组织损伤小鼠模型中持续性 SA 感染的解决率。