Linezolid decreases susceptibility to secondary bacterial pneumonia postinfluenza infection in mice through its effects on IFN-γ

J Immunol. 2013 Aug 15;191(4):1792-9. doi: 10.4049/jimmunol.1300180. Epub 2013 Jul 5.

Abstract

Influenza infection predisposes patients to secondary bacterial pneumonia that contributes significantly to morbidity and mortality. Although this association is well documented, the mechanisms that govern this synergism are poorly understood. A window of hyporesponsiveness following influenza infection has been associated with a substantial increase in local and systemic IFN-γ concentrations. Recent data suggest that the oxazolidinone antibiotic linezolid decreases IFN-γ and TNF-α production in vitro from stimulated PBMCs. We therefore sought to determine whether linezolid would reverse immune hyporesponsiveness after influenza infection in mice through its effects on IFN-γ. In vivo dose-response studies demonstrated that oral linezolid administration sufficiently decreased bronchoalveolar lavage fluid levels of IFN-γ at day 7 postinfluenza infection in a dose-dependent manner. The drug also decreased morbidity as measured by weight loss compared with vehicle-treated controls. When mice were challenged intranasally with Streptococcus pneumoniae 7 d postinfection with influenza, linezolid pretreatment led to decreased IFN-γ and TNF-α production, decreased weight loss, and lower bacterial burdens at 24 h postbacterial infection in comparison with vehicle-treated controls. To determine whether these effects were due to suppression of IFN-γ, linezolid-treated animals were given intranasal instillations of rIFN-γ before challenge with S. pneumoniae. This partially reversed the protective effects observed in the linezolid-treated mice, suggesting that the modulatory effects of linezolid are mediated partially by its ability to blunt IFN-γ production. These results suggest that IFN-γ, and potentially TNF-α, may be useful drug targets for prophylaxis against secondary bacterial pneumonia following influenza infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / administration & dosage
  • Acetamides / pharmacology
  • Acetamides / therapeutic use*
  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Bacterial Load
  • Bronchoalveolar Lavage Fluid / chemistry
  • CD4 Lymphocyte Count
  • Coinfection / prevention & control*
  • Disease Susceptibility
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Female
  • Influenza A virus / isolation & purification
  • Influenza A virus / physiology
  • Interferon-gamma / analysis
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interferon-gamma / physiology*
  • Interferon-gamma / therapeutic use
  • Linezolid
  • Lung / microbiology
  • Lung / virology
  • Mice
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections / complications*
  • Oxazolidinones / administration & dosage
  • Oxazolidinones / pharmacology
  • Oxazolidinones / therapeutic use*
  • Pneumonia, Pneumococcal / etiology
  • Pneumonia, Pneumococcal / prevention & control*
  • Recombinant Proteins / therapeutic use
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Viral Load
  • Virus Replication / drug effects

Substances

  • Acetamides
  • Anti-Bacterial Agents
  • Oxazolidinones
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Linezolid