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

• 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
• 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

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.

来自最近主要流行病的证据表明，直接的病毒细胞病变和炎症介导的组织损伤是同样重要的因素，增强宿主的致死性。因此，已经提出了针对严重呼吸道感染的抑制过度免疫损伤的治疗策略。虽然流感感染细胞的清除主要是由细胞毒性CD 8 + T细胞介导的，但现在已经确立的抗病毒宿主应答对先天性和适应性免疫区室的依赖性表明，利用先天性免疫可能形成开发有效疫苗和新型治疗方法的基础。白细胞从血液中早期募集到组织感染部位是先天免疫应答的标志。然而，目前尚不清楚凋亡免疫细胞在消退阶段如何在炎症组织中被去除-这是我们理解和操纵炎症性疾病的基本过程。尽管最近的研究进展有关吞噬去除凋亡细胞，可视化的动态细胞清除过程中，在体内一直是极具挑战性的。在这里，我们建议开发一种新的活体多光子显微镜（IV-MPM）系统，以解决关键的知识差距，在流感感染过程中的先天免疫细胞的功能和命运，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（气管）和下（肺）气道流感感染消退期间原位观察中性粒细胞增多症，以及（2）开发一种新的组织驻留吞噬细胞命运图测定法，以研究中性粒细胞增多症的免疫学后果。在小鼠流感感染模型中使用这些新方法，我们将能够识别流感感染期间先天免疫系统和适应性免疫系统之间的新相互作用。鉴于病毒感染过程中动态免疫调节特性的重要性，开发新的研究工具来阐明感染部位先天免疫和效应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应答的基础以及提高我们开发依赖于此类细胞介导应答的新通用疫苗的能力至关重要。