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. While 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 IFNγ concentrations. Recent data suggests that the oxazolidinone antibiotic linezolid decreases IFNγ and TNFα production in vitro from stimulated peripheral blood mononuclear cells. We therefore sought to determine whether linezolid would reverse immune hyporesponsiveness after influenza infection in mice through its effects on IFNγ. In vivo dose response studies demonstrated that oral linezolid administration sufficiently decreased bronchoalveolar lavage fluid levels of IFNγ at day 7 post-influenza infection in a dose-dependent manner. The drug also decreased morbidity as measured by weight loss compared to vehicle-treated controls. When mice were challenged intranasally with S. pneumoniae 7 days after infection with influenza, linezolid pre-treatment led to decreased IFNγ and TNFα production, decreased weight loss, and lower bacterial burdens at 24 hours post bacterial infection in comparison to vehicle-treated controls. To determine whether these effects were due to suppression of IFNγ, linezolid-treated animals were given intranasal instillations of recombinant IFNγ 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 IFNγ production. These results suggest that IFNγ, and potentially TNFα, may be useful drug targets for prophylaxis against secondary bacterial pneumonia following influenza infection.

Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells

“…The immunosuppressive effect of IFN-γ was unexpected, but our findings build on prior reports of immunosuppression by IFN-γ. In influenza and secondary streptococcal pneumonia, IFN-γ suppressed macrophage phagocytosis by downregulating expression of the scavenger receptor MARCO (50,51). The immunosuppressive mechanisms driven by mTOR and IFN-γ must vary by context, since in our study the expression of surface receptors did not explain impaired phagocytosis.…”

Allergic Airway Disease Prevents Lethal Synergy of Influenza A Virus-Streptococcus pneumoniae Coinfection

“…Interferon gamma (IFN-γ) has been implicated in influenza virus-induced immune suppression during secondary S. pneumoniae infection (4, 16, 26, 27). We therefore measured pulmonary IFN-γ protein concentrations.…”

The immunology of influenza virus-associated bacterial pneumonia

“…Azithromycin alone reduced S. pneumonia burden, but did not improve lung injury [13,52]. Linezolid, an antibiotic that is active against MRSA by binding to the 50S ribosomal subunit and inhibiting protein synthesis, has also been shown to reduce secondary bacterial pneumonia in experimental models by attenuating IFNγ expression [53]. Mice treated with recombinant IFNγ prior to bacterial challenge with S. pneumoniae seven days post-influenza virus infection showed partially reversed protective effects of linezolid.…”