1918 pandemic influenza virus and Streptococcus pneumoniae coinfection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans

To study bacterial coinfection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus followed by Streptococcus pneumoniae 72 h later. Coinfected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in coinfected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor (F3) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in coinfected mice. Lung sections of SP-positive 1918 autopsy cases showed extensive thrombi and prominent staining for F3 in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to coinfection-positive 2009 pandemic H1N1 autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and SP coinfection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis.