title: Influenza A and methicillin-resistant Staphylococcus aureus co-infection in rhesus macaques - A model of severe pneumonia.
abstract: BACKGROUND
  Influenza results in up to 500,000 deaths annually. Seasonal influenza vaccines have an estimated 60% effectiveness, but provide little or no protection against novel subtypes, and may be less protective in high-risk groups. Neuraminidase inhibitors are recommended for the treatment of severe influenza infection, but are not proven to reduce mortality in severe disease. Preclinical models of severe influenza infection that closely correlate to human disease are needed to assess efficacy of new vaccines and therapeutics.
  
  
  METHODS
  We developed a nonhuman primate model of influenza and bacterial co-infection that recapitulates severe pneumonia in humans. Animals were infected with influenza A virus via intra-bronchial or small-particle aerosol inoculation, methicillin-resistant Staphylococcus aureus, or co-infected with influenza and methicillin-resistant S. aureus combined. We assessed the severity of disease in animals over the course of our study using tools available to evaluate critically ill human patients including high-resolution computed tomography imaging of the lungs, arterial blood gas analyses, and bronchoalveolar lavage.
  
  
  RESULTS
  Using an intra-bronchial route of inoculation we successfully induced severe pneumonia following influenza infection alone and following influenza and bacterial co-infection. Peak illness was observed at day 6 post-influenza infection, manifested by bilateral pulmonary infiltrates and hypoxemia. The timing of radiographic and physiologic manifestations of disease in our model closely match those observed in severe human influenza infection.
  
  
  CONCLUSIONS
  This was the first nonhuman primate study of influenza and bacterial co-infection where high-resolution computed tomography scanning of the lungs was used to quantitatively assess pneumonia over the course of illness and where hypoxemia was correlated with pneumonia severity. With additional validation this model may serve as a pathway for regulatory approval of vaccines and therapeutics for the prevention and treatment of severe influenza pneumonia.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA; Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: chertowd@cc.nih.gov.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Chertow
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA; Integrated Research Facility-Frederick, National Institutes of Health, Frederick, 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, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zong-Mei
authors.initials: ZM
authors.lastname: Sheng
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Pujanauski
authors.affiliation: Integrated Research Facility-Frederick, National Institutes of Health, Frederick, MD, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Cooper
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA; Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nogee
authors.affiliation: Integrated Research Facility-Frederick, National Institutes of Health, Frederick, MD, USA.
authors.forename: Marisa St
authors.initials: MS
authors.lastname: Claire
authors.affiliation: Center for Infectious Disease Imaging, RAD&IS, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Solomon
authors.affiliation: Integrated Research Facility-Frederick, National Institutes of Health, Frederick, MD, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Perry
authors.affiliation: Integrated Research Facility-Frederick, National Institutes of Health, Frederick, MD, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Sayre
authors.affiliation: Integrated Research Facility-Frederick, National Institutes of Health, Frederick, MD, USA.
authors.forename: Krisztina B
authors.initials: KB
authors.lastname: Janosko
authors.affiliation: Integrated Research Facility-Frederick, National Institutes of Health, Frederick, MD, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Lackemeyer
authors.affiliation: Integrated Research Facility-Frederick, National Institutes of Health, Frederick, MD, USA.
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Bohannon
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Kash
authors.affiliation: Integrated Research Facility-Frederick, National Institutes of Health, Frederick, MD, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jahrling
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jeffery K
authors.initials: JK
authors.lastname: Taubenberger
mesh_terms: D000818:Animals; D060085:Coinfection; D006801:Humans; D009980:Influenza A virus / Q000472:pathogenicity; D007252:Influenza Vaccines; D007251:Influenza, Human / Q000150:complications / Q000382:microbiology; D008168:Lung / Q000382:microbiology / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000472:pathogenicity; D023421:Models, Animal; D009976:Orthomyxoviridae Infections / Q000150:complications*; D011023:Pneumonia, Staphylococcal / Q000150:complications*; D011024:Pneumonia, Viral / Q000150:complications*; D000072078:Positron Emission Tomography Computed Tomography
chemical_list: D007252:Influenza Vaccines
keywords: Co-infection; Influenza; Pneumonia; Therapies; Vaccines