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Sub-phenotyping pneumonia by lung pathobiology

通过肺部病理学对肺炎进行亚表型分析

基本信息

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
项目类别：
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

项目摘要

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.

项目总结