Sub-phenotyping pneumonia by lung pathobiology

通过肺部病理学对肺炎进行亚表型分析

• 批准号: 10749997
• 负责人: Bradley Hiller
• 金额: $ 6.91万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749997
• 关键词: 2019-nCoV; Age; Air; Alveolar; Alveolus; Autopsy; Biology; Blood; C57BL/6 Mouse; Cause of Death; Clinical; Clinical Trials; Coagulation Process; Deposition; Development; Elderly; Escherichia coli; Feedback; Fibrin; Freezing; Functional disorder; Histopathology; Human; Immune; Immune response; Immunohistochemistry; Infection; Infiltration; Influenza A virus; Klebsiella pneumoniae; Life; Link; Lung; Lung infections; Lymphocyte; Lymphocytic Infiltrate; Measures; Mediating; Mediator; Modeling; Mus; Neutrophil Activation; Neutrophil Infiltration; Neutrophilia; Pathogenesis; Pathology; Patient Care; Patients; Pattern; Phenotype; Plasma; Pneumonia; Polymers; Pulmonary Pathology; Research Priority; Sampling; Sendai virus; Serotyping; Severities; Stains; Streptococcus pneumoniae; Structure of parenchyma of lung; Testing; Therapeutic; Tissue Sample; Training; Variant; Virus Diseases; design; experience; human model; improved; mouse model; neutrophil; pathogen; pneumonia model; pneumonia treatment; respiratory pathogen; response; single nucleus RNA-sequencing

Project Summary Pneumonia induces heterogeneous responses in the lung, resulting in pathobiological sub- phenotypes. Because these sub-phenotypes are difficult to identify in patients and are responsive to different treatments, elucidating and characterizing lung pathology sub-phenotypes is a major research priority. Mouse models used to study pneumonia may capture some, but not all, human pneumonia sub-phenotype features, but this has yet to be formally examined. To characterize the lung biology underlying human pneumonia sub-phenotypes, we analyzed autopsy tissue samples from hundreds of elderly subjects who died with pneumonia using histopathology and immunohistochemistry. We observed broad heterogeneous lung pathobiologies and diverse immune landscapes across these human lung samples, including differences in lymphocyte and neutrophil infiltration. Increased fibrin in the lung parenchyma positively correlated with neutrophil infiltration, suggesting a link between fibrin accumulation and neutrophil recruitment or activity. To determine which aspects of human pneumonia sub-phenotypes are recapitulated or missed in commonly used mouse models of pneumonia, we characterized pulmonary histopathology in mice with severe and diverse pneumonias caused by Streptococcus pneumoniae (Sp) or influenza A virus (IAV) infection. IAV infection was characterized by pulmonary lymphoplasmacytosis, whereas Sp3-infected lungs were instead inundated with neutrophils and high intra-alveolar fibrin deposition reflecting the fibrin-neutrophil association observed in human autopsy samples. To investigate the mechanisms promoting pneumonia sub-phenotype diversity in the lung, we propose in this F32 the following aims to test the hypotheses that 1) age, previous infection experience, and additional pathogens will reveal additional and diverse pneumonia sub-phenotypes reflected in our human pneumonia samples, and 2) severing the interactions between polymerized fibrin and neutrophils in the airspace will decrease the pathogenesis of pneumonia mediated by Sp but not IAV. Advancing pneumonia models to better reflect human lung biology will help define mechanisms for the establishment of specific pneumonia sub-phenotypes and will be essential for targeted design and proper utilization of host-directed pneumonia therapeutics.

项目摘要 肺炎在肺中诱导异质反应，导致病理生物学亚 表型。因为这些子表型在患者中难以识别，并且对 不同的治疗方法，阐明和表征肺病理亚表征是一项重大研究 优先事项。用于研究肺炎的小鼠模型可能会捕获一些但不是全部的人类肺炎 子表型特征，但这尚未正式检查。表征肺生物学 潜在的人肺炎亚表型，我们分析了数百种的尸检组织样品 使用组织病理学和免疫组织化学死于肺炎的老年受试者。我们 观察到广泛的异质性肺病原体和各种免疫景观 人肺样本，包括淋巴细胞和中性粒细胞浸润的差异。增加纤维蛋白 肺实质与中性粒细胞浸润正相关，表明纤维蛋白之间有联系 积累和中性粒细胞募集或活动。确定人肺炎的哪些方面 在常用的肺炎小鼠模型中概括或错过了亚表格型，我们 在严重和多种肺炎的小鼠中表征了肺组织病理学 肺炎链球菌（SP）或流感A病毒（IAV）感染。 IAV感染的特征是 肺淋巴细胞术，而SP3感染的肺则被嗜中性粒细胞淹没 和高肺泡内纤维蛋白沉积，反映在人类 尸检样品。研究促进肺炎亚表型多样性的机制 肺，我们在此F32中提出以下目的是测试假设1）年龄，先前的感染 经验和其他病原体将揭示其他多样的肺炎亚表型 反映在人类肺炎样品中，2）切断聚合纤维蛋白之间的相互作用 空域中的嗜中性粒细胞会减少由SP介导的肺炎的发病机理，但不是 IAV。推进肺炎模型以更好地反映人肺生物学将有助于定义机制 为了建立特定的肺炎子表型，对于目标设计至关重要 并适当利用宿主定向的肺炎疗法。