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

基本信息

批准号：
10212940
负责人：
J. Kent Leach
金额：
$ 37.81万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212940
关键词：
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 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 Infectious Skin Diseases Inflammasome Inflammation Innate Immune Response Interleukin 2 Receptor 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 Resolution Role Signal Transduction Site Skin Tissue Soft Tissue Infections Source Staphylococcus aureus Staphylococcus aureus infection TLR2 gene Testing Therapeutic Tissues Toxin Transgenic Organisms Virulence Virulence Factors Virulent Wound Infection Wound models acute wound alpha Toxin bactericide cellular engineering chronic infection chronic wound combat enhancing factor healing hematopoietic differentiation human model imaging approach immune function immunoregulation improved in vivo innovation macrophage methicillin resistant Staphylococcus aureus microbial neutrophil new technology non-invasive monitor novel novel therapeutic intervention optical imaging pathogen prevent progenitor recruit resistant strain response skin wound stem cell therapy trait wound wound healing

项目摘要

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。