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性反应，导致病理生物学亚组化。 表型因为这些亚表型在患者中难以识别，并且对 不同的治疗，阐明和表征肺病理亚表型是一个主要的研究 要务用于研究肺炎的小鼠模型可能会捕获一些，但不是所有的人类肺炎 亚表型特征，但这还有待正式研究。描述肺部生物学特征 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检测死于肺炎的老年受试者。我们 观察到广泛的异质性肺部病理生物学和不同的免疫景观在这些 人肺样品，包括淋巴细胞和中性粒细胞浸润的差异。纤维蛋白增加， 肺实质与中性粒细胞浸润呈正相关，提示纤维蛋白 聚集和中性粒细胞募集或活性。为了确定人类肺炎的哪些方面 在常用的小鼠肺炎模型中， 在患有严重和多样性肺炎的小鼠中的特征性肺组织病理学 肺炎链球菌（Sp）或甲型流感病毒（IAV）感染。IAV感染的特征是： 肺淋巴浆细胞增多，而Sp3感染的肺则充满了中性粒细胞 肺泡内纤维蛋白沉积高，反映了在人体中观察到的纤维蛋白-中性粒细胞结合 尸检样本探讨促进肺炎亚表型多样性的机制， 肺，我们在本F32中提出以下目的来检验假设：1）年龄，既往感染 经验，和其他病原体将揭示额外的和不同的肺炎亚表型 反映在我们的人类肺炎样本，和2）切断聚合纤维蛋白之间的相互作用， 空气中的中性粒细胞可减少Sp介导的肺炎的发病， IAV推进肺炎模型以更好地反映人类肺部生物学将有助于确定机制 用于建立特定的肺炎亚表型，并且对于靶向设计至关重要 以及正确使用宿主导向的肺炎治疗剂。