title: 1918 pandemic influenza virus and Streptococcus pneumoniae co-infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans.
abstract: To study bacterial co-infection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by Streptococcus pneumoniae (SP) 72 h later. Co-infected 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 co-infected 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 co-infected 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 co-infection-positive 2009 pandemic H1N1 autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and SP co-infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis.
authors.affiliation: Institute for Systems Biology, Seattle, WA, USA.
authors.forename: Kathie-Anne
authors.initials: KA
authors.lastname: Walters
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Office of Blood Research and Review, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Felice
authors.initials: F
authors.lastname: D'Agnillo
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, 20892, USA.
authors.forename: Zong-Mei
authors.initials: ZM
authors.lastname: Sheng
authors.affiliation: Critical Care Medicine Department, National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Kindrachuk
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, 20892, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Schwartzman
authors.affiliation: Institute for Systems Biology, Seattle, WA, USA.
authors.forename: Rolf E
authors.initials: RE
authors.lastname: Kuestner
authors.affiliation: Critical Care Medicine Department, National Institutes of Health (NIH), Bethesda, MD, USA.|Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, 20892, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Chertow
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Office of Blood Research and Review, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Basil T
authors.initials: BT
authors.lastname: Golding
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, 20892, USA.
authors.forename: Jeffery K
authors.initials: JK
authors.lastname: Taubenberger
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, 20892, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Kash
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D060085:Coinfection / Q000150:complications*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053118:Influenza A Virus, H1N1 Subtype; D064149:Influenza Pandemic, 1918-1919; D007251:Influenza, Human / Q000150:complications / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000382:microbiology* / Q000473:pathology; D011008:Pneumococcal Infections / Q000150:complications / Q000382:microbiology* / Q000473:pathology; D011655:Pulmonary Embolism / Q000382:microbiology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013296:Streptococcus pneumoniae
keywords: 1918 influenza; Streptococcus pneumoniae; co-infection; extrinsic pathway of coagulation; inflammation; pulmonary thrombosis