Neutrophil Dynamics in Nasal Mucosa

鼻粘膜中性粒细胞动态

• 批准号: 10638705
• 负责人: ULRICH H VON ANDRIAN
• 金额: $ 68.93万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-03 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638705
• 关键词: Address; Adhesions; Adoptive Transfer; Affect; Air; Anatomy; Antigen-Presenting Cells; Antigens; Bacterial Infections; Behavior; Blood; Blood Vessels; Bone Marrow; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Candida albicans; Cells; Cephalic; Characteristics; Chlamydia muridarum; Clinical; Complex; Data; Disease; Environment; Exposure to; Flow Cytometry; Gene Expression Profile; Germ-Free; Goals; Health; Homeostasis; Homing; Host Defense; Human; Hypersensitivity; ITGAX gene; Immune; Immune response; Immunobiology; Immunologic Surveillance; Immunologics; Infection; Inhalation; Innate Immune Response; Leukocytes; Mammals; Microcirculation; Microscopy; Modeling; Molecular; Morphology; Mucous Membrane; Mus; Mycoses; Nasal cavity; Neutrophil Infiltration; Nose; Organ; Parabiosis; Pathologic; Phenotype; Physiological; Play; Population; Property; Respiratory Tract Infections; Role; Sensory; Stimulus; Streptococcus pneumoniae; Structure of mucous membrane of nose; Submucosa; Surface; Surveys; T cell response; Testing; Tissues; Upper respiratory tract; Vaccines; Vertebrates; Work; adaptive immune response; conditioning; experimental study; extracellular; improved; intravital microscopy; microbial; microbiome; microorganism interaction; migration; neutrophil; novel; opportunistic pathogen; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; progenitor; recruit; respiratory pathogen; single-cell RNA sequencing; source localization; transcriptome sequencing; transcriptomics

The nasal mucosa (NM) has several critical physiologic functions, including as a chemosensory organ, as a filter and conditioning surface of inhaled air for the lower airways, and as a first line of defense against airborne infections. In mammals, the nasal passage is anatomically complex, with different sub-compartments with distinct morphological and cellular features that may exert specialized, but as yet poorly understood, functions. Owing to its constant exposure to ever-changing environments, the NM is arguably the most frequently infected tissue in mammals. Aside from being a preferred initial target for many fungal, viral and bacterial pathogens, some of which may subsequently spread to the lower airways, blood, brain or other cranial regions, the nasal cavity is also colonized by a specialized microbiome that can serve as a reservoir for opportunistic pathogens. Despite the NM's importance for human health, little is known about the mechanisms by which local immune responses are initiated and/or regulated. Arguably, the NM must possess specialized features to enable appropriate innate and adaptive immune responses against a broad variety of challenges. The NM is known to harbor a population of subepithelial extravascular immune cells, but their origin, composition, and role at steady-state and in pathologic conditions are poorly understood. To address this issue, a novel intravital microscopy (IVM) model was devised to track the dynamic behavior of leukocytes in the NM of living mice. Preliminary results indicate that murine steady-state NM harbors a prominent population of extravascular neutrophils (EVN) that are abundant in both conventional and germ-free mice, suggesting that their presence is not driven by microbial stimuli. Furthermore, nasal EVN can be subdivided into three phenotypically distinct subsets: one population (termed N1) is CD11bint Ly6Gint, while the other two subsets are both CD11bhi Ly6Ghi and distinguishable by the absence (N2) or presence (N3) of CD11c and SiglecF. The primary objective of this project is to define how these unusual EVN subsets arise, how they respond to infectious challenges and what role they play in health and disease. It is hypothesized that each nasal EVN subset has a distinct origin, accesses the NM by discrete mechanisms, and exerts specialized functions in tissue homeostasis and in host defense against microbial infections. To test this hypothesis, Aim 1 will explore the origin and migratory properties of steady-state nasal EVN subsets, whereas Aim 2 will define the function of each EVN subset in homeostasis and after intranasal pathogen challenge. Results from the proposed work may not only improve our understanding of the NM as a critical barrier tissue, but also shed new light on immunological mechanisms that may impact the efficacy of nasal vaccines and on pathologic conditions affecting the nasal cavity such as allergies and a host of respiratory infections.

鼻粘膜 (NM) 具有多种重要的生理功能，包括作为化学感应器官、作为下呼吸道吸入空气的过滤器和调节表面，以及作为抵御空气传播感染的第一道防线。在哺乳动物中，鼻道在解剖学上很复杂，具有不同的子区室，具有不同的形态和细胞特征，这些特征可能发挥专门的但迄今知之甚少的功能。由于 NM 不断暴露在不断变化的环境中，NM 可以说是哺乳动物中最常被感染的组织。鼻腔除了是许多真菌、病毒和细菌病原体的首选初始目标（其中一些可能随后扩散到下呼吸道、血液、大脑或其他颅骨区域）外，还被一种特殊的微生物群定殖，该微生物群可以充当机会性病原体的储存库。尽管 NM 对人类健康很重要，但人们对局部免疫反应启动和/或调节的机制知之甚少。可以说，NM 必须具备专门的功能，才能针对各种挑战做出适当的先天和适应性免疫反应。众所周知，NM 含有一群上皮下血管外免疫细胞，但人们对它们的起源、组成以及在稳态和病理条件下的作用知之甚少。为了解决这个问题，设计了一种新型活体显微镜 (IVM) 模型来跟踪活体小鼠 NM 中白细胞的动态行为。初步结果表明，小鼠稳态 NM 含有大量血管外中性粒细胞 (EVN)，这些细胞在传统小鼠和无菌小鼠中都很丰富，这表明它们的存在不是由微生物刺激驱动的。此外，鼻部 EVN 可以细分为三个表型不同的亚群：一个群体（称为 N1）是 CD11bint Ly6Gint，而其他两个亚群都是 CD11bhi Ly6Ghi，可通过 CD11c 和 SiglecF 的缺失（N2）或存在（N3）来区分。该项目的主要目标是确定这些不寻常的 EVN 子集是如何产生的、它们如何应对感染挑战以及它们在健康和疾病中发挥什么作用。据推测，每个鼻部 EVN 亚群都有不同的起源，通过离散机制进入 NM，并在组织稳态和宿主防御微生物感染方面发挥专门的功能。为了检验这一假设，目标 1 将探索稳态鼻 EVN 亚群的起源和迁移特性，而目标 2 将定义每个 EVN 亚群在稳态和鼻内病原体攻击后的功能。拟议工作的结果不仅可以提高我们对 NM 作为关键屏障组织的理解，而且还可以为可能影响鼻疫苗功效的免疫机制以及影响鼻腔的病理状况（例如过敏和宿主）提供新的见解。呼吸道感染。