Engineering the innate immune response to Staphaureus infection

设计针对葡萄球菌感染的先天免疫反应

• 批准号: 9401775
• 负责人: J. Kent Leach
• 金额: $ 38.07万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401775
• 关键词: Acute; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Bacteria; Bacterial Antigens; Biological Response Modifier Therapy; Bioreactors; Bone Marrow; CD34 gene; Cell Communication; Cell Differentiation process; Cell Therapy; Cell Wall; Cells; Chimera organism; Communities; Complication; Cutaneous; Data; Detection; Engineering; Generations; Genetic Engineering; Goals; Granulopoiesis; Hematopoietic stem cells; Hemolysin; Hospitals; Host Defense; Human; Hybrids; Immune; Immune response; Immune signaling; Immunodeficient Mouse; Immunofluorescence Immunologic; Immunosuppression; Impaired wound healing; In Vitro; Infection; Inflammasome; Inflammation; Innate Immune Response; Knock-in Mouse; Knowledge; Lead; Leukocytes; Mesenchymal Stem Cells; Methicillin Resistance; Microfluidics; Modeling; Monitor; Multi-Drug Resistance; Muramidase; Mus; Myelogenous; Myeloid Progenitor Cells; Neutrophil Infiltration; Organ; Peptidoglycan; Process; Recruitment Activity; Resolution; Role; Signal Transduction; Site; Skin Tissue; Skin wound; Soft Tissue Infections; Source; Staphylococcus aureus; Stem cells; TLR2 gene; Testing; Therapeutic; Tissues; Toxin; Transgenic Organisms; Virulence; Virulence Factors; Virulent; Wound Healing; Wound Infection; alpha Toxin; bactericide; cellular engineering; chronic wound; combat; enhancing factor; healing; imaging approach; immune function; immunoregulation; improved; in vivo; innovation; macrophage; methicillin resistant Staphylococcus aureus; microbial; neutrophil; new technology; novel; novel therapeutics; optical imaging; pathogen; prevent; progenitor; resistant strain; response; trait; wound

ABSTRACT Staphylococcus aureus (SA) is a major cause of cutaneous infections. Virulent community-acquired methicillin-resistant SA (MRSA) is the most common source of skin and soft tissue infections in U.S. hospitals. Prompt recruitment of polymorphonuclear (PMN) leukocytes in sufficient numbers to the site of infection is critical for controlling MRSA infection and preventing dissemination to vital organs. Unexpectedly, we recently discovered that hematopoietic stem and progenitor cells (HSPCs) are also recruited to wounds, and these cells detect bacterial antigens and virulence factors, and augment PMN numbers necessary to resolve a MRSA infected wound. The signaling process eliciting an increase in myeloid recruitment and differentiation of HSPC within the wound was found to involve toll-like receptor 2 (TLR2) detection of peptidoglycans derived from the gram-positive cell wall and released within the wound. We propose that this newly discovered host immune trait is an adaption to effectively overcome immune suppression by MRSA virulence factors such as α-hemolysin toxin (AT) that blocks PMN recruitment by lysing perivascular macrophages that help guide them to sites of infection. The central hypothesis governing this proposal is that immune-modulation that tunes PMN number and antibacterial activity against MRSA infection can hasten clearance and healing. This proposal will utilize our innovative model of wound infection that employs genetically-engineered bioluminescent bacteria and a transgenic lysozyme- M-EGFP knock-in mouse that produces fluorescent mature PMN. This model will be used in conjunction with advanced in vivo whole animal optical imaging to noninvasively and longitudinally monitor bacterial burden and immune responses. A translational goal will be the implementation of human CD34+ HSPC myeloid expansion to evaluate the therapeutic potential of local PMN expansion to combat MRSA infection in an immunodeficient (NSG) mouse wound model.

摘要 金黄色葡萄球菌（Staphylococcus aureus，SA）是皮肤感染的主要原因。毒力 社区获得性耐甲氧西林金黄色葡萄球菌（MRSA）是皮肤感染的最常见来源。 和软组织感染。多形核细胞的迅速募集 (PMN)足够数量的白细胞到感染部位对于控制 MRSA感染和防止传播到重要器官。没想到，我们最近 发现造血干细胞和祖细胞（HSPCs）也被招募， 伤口，这些细胞检测细菌抗原和毒力因子， 解决MRSA感染伤口所需的PMN数量。的信令流程 引起伤口内HSPC的髓样募集和分化增加 发现涉及Toll样受体2（TLR 2）检测来自 革兰氏阳性细胞壁并在伤口内释放。我们建议， 发现的宿主免疫特性是一种适应，可以有效地克服免疫 MRSA毒力因子如α-溶血素毒素（AT）抑制PMN 通过溶解血管周围的巨噬细胞，帮助引导它们到 感染支配这一提议的中心假设是， 调节PMN数量和抗MRSA感染的抗菌活性可以加速 清除和愈合。这项建议将利用我们的创新模型的伤口感染 它采用了基因工程生物发光细菌和转基因溶菌酶， 产生荧光成熟PMN的M-EGFP敲入小鼠。这一模式将 与先进的体内整体动物光学成像结合使用， 并纵向监测细菌负荷和免疫应答。翻译目标 将实施人CD 34 + HSPC髓系扩增，以评估 局部中性粒细胞扩增对抗MRSA感染的治疗潜力 免疫缺陷（NSG）小鼠伤口模型。