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.

项目概要 肺炎引起肺部异质反应，导致病理亚型 表型。因为这些亚表型很难在患者中识别并且对 不同的治疗方法、阐明和表征肺部病理亚表型是一项重大研究 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 亚表型特征，但这尚未得到正式检验。描述肺生物学特征 为了了解潜在的人类肺炎亚表型，我们分析了数百个尸检组织样本 使用组织病理学和免疫组织化学研究死于肺炎的老年受试者。我们 观察到广泛的异质肺病理学和不同的免疫景观 人肺样本，包括淋巴细胞和中性粒细胞浸润的差异。纤维蛋白含量增加 肺实质与中性粒细胞浸润呈正相关，表明纤维蛋白之间存在联系 积累和中性粒细胞募集或活动。确定人类肺炎的哪些方面 在常用的肺炎小鼠模型中，亚表型被重演或遗漏，我们 患有由以下原因引起的严重和多种肺炎的小鼠的肺部组织病理学特征 肺炎链球菌 (Sp) 或甲型流感病毒 (IAV) 感染。 IAV 感染的特点是 肺淋巴浆细胞增多症，而 Sp3 感染的肺部则被中性粒细胞淹没 和高肺泡内纤维蛋白沉积反映了在人类中观察到的纤维蛋白-中性粒细胞关联 尸检样本。探讨促进肺炎亚表型多样性的机制 肺，我们在此 F32 中提出以下旨在检验以下假设：1) 年龄、既往感染情况 经验和其他病原体将揭示更多和多样化的肺炎亚表型 反映在我们的人类肺炎样本中，2) 切断聚合纤维蛋白之间的相互作用 空腔中的中性粒细胞会减少 Sp 介导的肺炎的发病机制，但不会减少 IAV。改进肺炎模型以更好地反映人类肺部生物学将有助于定义机制 对于建立特定的肺炎亚表型，对于针对性设计至关重要 以及正确利用针对宿主的肺炎疗法。