title: Linezolid decreases susceptibility to secondary bacterial pneumonia postinfluenza infection in mice through its effects on IFN-γ.
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.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Breslow-Deckman
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Mattingly
authors.forename: Susan E
authors.initials: SE
authors.lastname: Birket
authors.forename: Samantha N
authors.initials: SN
authors.lastname: Hoskins
authors.forename: Tam N
authors.initials: TN
authors.lastname: Ho
authors.forename: Beth A
authors.initials: BA
authors.lastname: Garvy
authors.forename: David J
authors.initials: DJ
authors.lastname: Feola
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D058491:Bacterial Load; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018791:CD4 Lymphocyte Count; D060085:Coinfection / Q000517:prevention & control*; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D009980:Influenza A virus / Q000302:isolation & purification / Q000502:physiology; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D000069349:Linezolid; D008168:Lung / Q000382:microbiology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000150:complications*; D023303:Oxazolidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011018:Pneumonia, Pneumococcal / Q000209:etiology / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000069349:Linezolid