Visualizing the resolution of innate immune responses during influenza infection

可视化流感感染期间先天免疫反应的解决

基本信息

批准号：
9899365
负责人：
Minsoo Kim
金额：
$ 23.1万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899365
关键词：
Address Antigen-Presenting Cells Antiviral Agents Apoptosis Apoptotic Area Biochemical Process Cell Communication Cell Differentiation process Cell physiology Cells Cessation of life Data Dependence Detection Development Disease Epithelial Epithelium Excision Funding Opportunities Immune Immune response Immunologics In Situ Infection Inflammation Inflammatory Influenza Injury Innate Immune Response Knowledge Mediating Microscopy Modeling Molecular Morbidity - disease rate Mus Natural Immunity Neutrophil Activation Neutrophil Infiltration Neutrophilic Infiltrate Organ failure Patients Pattern Peripheral Phagocytes Phase Process Property Resolution Role Site System T cell response T-Cell Activation T-Lymphocyte Testing Tissues Trachea United States Vaccination Vaccines Virus Virus Diseases Visualization adaptive immune response cell motility cytotoxic CD8 T cells effector T cell in vivo influenzavirus innate immune mechanisms lymph nodes migration monocyte mortality multi-photon neutrophil novel novel therapeutic intervention pandemic disease pathogen recruit repaired response universal vaccine

项目摘要

Evidence from recent major epidemics suggests that both direct viral cytopathicity and inflammation-mediated tissue damage are equally important factors that potentiate the host lethality. Thus, the therapeutic strategy to bridle excessive immune damage has been proposed for severe respiratory infections. While clearance of influenza-infected cells is primarily mediated by cytotoxic CD8+ T cells, the now well-established dependency of anti-viral host responses on both innate and adaptive immune compartments suggests that harnessing the innate immunity might form a basis for the development of effective vaccines and novel therapeutic approaches. Early recruitment of leukocytes from the blood to sites of tissue infection is a hallmark of innate immune responses. However, it is currently not known how apoptotic immune cells are removed within inflamed tissues during the resolution phase – a process fundamental to our understanding and manipulation of inflammatory diseases. Despite recent advances in studies concerning phagocytic removal of apoptotic cells, the visualization of the dynamic cell clearance process in vivo has been extremely challenging. Here we propose to develop a novel intravital multi-photon microscopy (IV-MPM) system to address critical knowledge gaps regarding the function and fate of innate immune cells during the influenza infection, and their roles in anti-viral immune responses. We will (1) develop the IV-MPM system to visualize in situ neutrophil efferocytosis during resolution of influenza infection in the upper (trachea) and lower (lung) airway, and (2) develop a novel tissue-resident phagocyte fate-mapping assay to study the immunological consequence of the neutrophil efferocytosis. With these new approaches in a mouse influenza infection model, we will be able to identify novel interactions between innate and adaptive immune systems during the influenza infection. Given the importance of dynamic immune modulatory properties during viral infections, the development of novel research tools to elucidate the relationship between innate immunity and effector T cell interactions at the site of infection is critical for deciphering the basis of productive and nonproductive adaptive immune responses and for advancing our capacity to develop new universal vaccines that rely on such cell mediated responses.

最近主要发作的证据表明，直接病毒细胞病变和炎症介导的组织损伤都是潜在宿主致死性的重要因素。这是针对严重的呼吸道感染提出了过多的免疫过滤的治疗策略。虽然受影响的受影响的受影响的细胞的清除主要由细胞毒性CD8+ T细胞介导，但现在抗病毒宿主反应对先天性和适应性免疫机构的良好依赖性表明，利用先天性免疫抑制可能会构成有效疫苗和新型治疗方法的发展的基础。从血液到组织感染部位的白细胞早期招募是先天免疫调查的标志。但是，目前尚不清楚在分辨率阶段如何在发炎的组织中去除凋亡的免疫细胞，这是我们对炎症性疾病的理解和操纵基本的过程。尽管在有关吞噬细胞的吞噬细胞去除的研究中最近取得了进步，但体内动态细胞清除过程的可视化仍然极为挑战。在这里，我们建议开发一种新型的插入式多光子显微镜（IV-MPM）系统，以解决有关在影响力感染的影响期间与先天免疫细胞功能和命运的关键知识差距，以及它们在抗病毒免疫反应中的作用。我们将（1）开发IV-MPM系统，以在上部（气管）和下部（肺）气道分辨出造影症感染期间可视化原位中性粒细胞效率，以及（2）发展了一种新型的居民居民吞噬吞噬型映射评估，以研究中性粒细胞症的免疫学后果。通过小鼠影响力感染模型中的这些新方法，我们将能够在影响力感染期间识别先天和适应性免疫系统之间的新型相互作用。鉴于在病毒感染过程中动态免疫调节特性的重要性，新型研究工具的开发以阐明先天免疫学和感染部位的效应T细胞相互作用之间的关系对于破译生产性和非生产性适应性免疫响应的基础至关重要