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.

抽象的 金黄色葡萄球菌（SA）是皮肤感染的主要原因。有力 耐甲氧西林的SA（MRSA）是最常见的皮肤来源 和美国医院的软组织感染。迅速招募多形刺激性 （PMN）足够数量到感染部位的白细胞对于控制至关重要 MRSA感染并防止向重要器官传播。出乎意料的是，我们最近 发现造血茎和祖细胞（HSPC）也被招募到 伤口，这些细胞检测细菌抗原和病毒因子，并增加 解决MRSA感染伤口所需的PMN数字。信号过程 引起伤口中HSPC的髓样募集和分化的增加 被发现涉及诸如收费受体2（TLR2）的检测 革兰氏阳性细胞壁并在伤口内释放。我们提出了这个新的 发现的宿主免疫特征是一种有效克服免疫的适应性 MRSA病毒因子的抑制，例如阻断PMN 通过裂解血管周围巨噬细胞招募，以帮助他们引导他们进入 感染。管理该提议的中心假设是免疫调节 调音PMN数量和针对MRSA感染的抗菌活性可以Haveten 清除和康复。该建议将利用我们的创新伤口感染模型 员工通过遗传设计的生物发光细菌和转基因溶菌酶 M-EGFP敲入小鼠，产生荧光成熟的PMN。这个模型将是 与先进的体内整个动物光学成像结合使用至无创 并纵向监测细菌燃烧和免疫反应。翻译目标 将是人类CD34+ HSPC髓样扩张的实施，以评估 局部PMN扩展的治疗潜力，以打击MRSA感染 免疫缺陷（NSG）小鼠伤口模型。