Alveolar Fibrin Deposition During Bacterial Pneumonia in Humans and Mice

Pulmonary infections induce heterogeneous immune responses in the lung, resulting in multiple pneumonia phenotypes. An etiological agent cannot be identified in the majority of pneumonia cases; thus, elucidating these heterogeneous lung pathobiologies for the development of host-directed therapies is a major research priority. To characterize the heterogeneity in human pneumonia pathobiology, we scored 20 pneumonia features across hundreds of autopsy tissue samples from elderly subjects who died with pneumonia. These pneumonia features varied significantly across our human lung samples, particularly the presence and severity of polymerized fibrin in the alveolar spaces. In our human pneumonia samples, alveolar fibrin deposition was most severe in the samples diagnosed with bronchopneumonia and positively-correlated with neutrophilia and necrosis, while it was less frequent in our samples diagnosed with interstitial pneumonia and negatively-correlated with lymphoplasmacytosis and fibrosis. To understand the mechanism and significance of alveolar fibrin deposition during pneumonia, we further characterized these features in C57BL/6 mice with severe pneumonias caused by Streptococcus pneumoniae (Sp), Escherichia coli (Ec), Klebsiella pneumoniae (Kp), influenza A virus (IAV), or SARS-CoV-2 (SCV2). Sp- and Ec-infected lungs were dominated by neutrophilic influx and high levels of polymerized fibrin in the alveolar spaces, reflecting the fibrin-neutrophil association observed in human autopsy samples, while Kp-, IAV-, and SCV2-infected lungs had little-to-no alveolar fibrin staining despite an abundance of fibrin in the vasculature. During Sp infection, fibrinogen was upregulated in the liver and significantly increased in the blood. RNA in situ hybridization of Sp-infected lungs revealed an upregulation of extrinsic coagulation factors that promote fibrin polymerization, including tissue factor (F3) in airway epithelial cells, F10 in recruited neutrophils, and F13a1 in myeloid cells, revealing potential mechanistic drivers of fibrin polymerization in the airspace. Together, these data demonstrate that (1) alveolar fibrin is observed in only a subset of human lungs with pneumonia, and (2) some pneumonia-causing pathogens, but not others, upregulate fibrinogen and promote cleaved fibrin polymerization in the alveolar spaces of mice. These mouse models can be used to elucidate the immunological and pathophysiological significance of this fibrin accumulation in a subset of pneumonias, which may provide additional targets for the development of host-directed therapies aiming to enhance or reduce alveolar fibrin deposition during pneumonia.