Abstract Pulmonary infections induce heterogeneous immune responses resulting in multiple pneumonia sub-phenotypes. An etiological agent cannot be identified in the majority of pneumonia cases; thus, characterizing these unique pneumonia sub-phenotypes and the mechanisms that drive them is critical for the development of clinical detection strategies and host-directed therapies. One prominent pneumonia sub-phenotype, necrosuppurative pneumonia, exhibits high necrosis (“necro-”), neutrophils and edema (“-suppurative”), and prominent fibrin clots in the alveolar airspace. These same features of human necrosuppurative pneumonia are modeled in Streptococcus pneumoniae (Sp)-infected mice, providing a valuable tool to delineate the mechanisms underlying the development of necrosuppurative pneumonia. Alveolar fibrin accumulation in Sp-infected lungs suggest contributions of the coagulation pathway may be active in the airspaces. During Sp infection, fibrinogen mRNA was induced in the liver and elevated in the blood. Tissue factor (TF, F3) initiates the extrinsic coagulation pathway and Sp infection induced high TF expression in lung epithelial cells, revealing that epithelial cells may drive the coagulation cascade and alveolar fibrin deposition during necrosuppurative pneumonia. In mice with an inducible deletion of epithelial TF (“F3epi mice”), there was a marked decrease in alveolar fibrin, neutrophils, and edema by histopathology. While Sp infection caused alveolar necrosis in wild-type mice, we instead observed type II epithelial cell hyperplasia in Sp-infected F3epi mice. Bacteria grew inexorably in the lungs and caused bacteremia in both wild-type and F3epi mice, revealing that epithelial TF modulates the host response to infection rather than altering bacterial burden or dissemination. Together, these data demonstrate that epithelial TF drives the alveolar fibrin, neutrophil accumulation, edema, and epithelial necrosis that are the defining features of necrosuppurative pneumonia caused by severe pneumococcal infection. This abstract is funded by: NIH/NHLBI and NIAID
Hiller et al. (Fri,) studied this question.