Sub-phenotyping pneumonia by lung pathobiology

点击翻译按钮获取中文摘要

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.