Abstract
BackgroundPoor interferon gamma (IFNγ) production during respiratory syncytial virus (RSV) is associated with prolonged viral clearance and increased disease severity in neonatal mice and humans. We previously showed that intra-nasal delivery of IFNγ significantly enhances RSV clearance from neonatal lungs prior to observed T-lymphocyte recruitment or activation, suggesting an innate immune mechanism of viral clearance. We further showed that alveolar macrophages dominate the RSV-infected neonatal airways relative to adults, consistent with human neonatal autopsy data. Therefore, the goal of this work was to determine the role of neonatal alveolar macrophages in IFNγ-mediated RSV clearance.MethodsClodronate liposomes, flow cytometry, viral plaque assays, and histology were used to examine the role of alveolar macrophages (AMs) and the effects of intra-nasal IFNγ in RSV infected neonatal Balb/c mice. The functional outcomes of AM depletion were determined quantitatively by viral titers using plaque assay. Illness was assessed by measuring reduced weight gain.ResultsAM activation during RSV infection was age-dependent and correlated tightly with IFNγ exposure. Higher doses of IFNγ more efficiently stimulated AM activation and expedited RSV clearance without significantly affecting weight gain. The presence of AMs were independently associated with improved RSV clearance, whereas AM depletion but not IFNγ exposure, significantly impaired weight gain in RSV-infected neonates.ConclusionWe show here for the first time, that IFNγ is critical for neonatal RSV clearance and that it depends, in part, on alveolar macrophages (AMs) for efficient viral clearing effects. Early reductions in viral burden are likely to have profound short- and long-term immune effects in the vulnerable post-natally developing lung environment. Studies are ongoing to elucidate the pathologic effects associated with early versus delayed RSV clearance in developing neonatal airways.
Highlights
Poor interferon gamma (IFNγ) production during respiratory syncytial virus (RSV) is associated with prolonged viral clearance and increased disease severity in neonatal mice and humans
Viral clearance capacity was determined in IFNγR knock-out (IFNγRKO) mice compared to wild-type
IFNγ concentrations in RSV- compared to mockinfected animals in BALF at 7dpi (Fig. 2c), which did not occur in neonatal mice infected at 2–4 days of age suggesting that RSV-mediated alveolar macrophages (AMs) activation is agedependent and may correlate with IFNγ
Summary
Poor interferon gamma (IFNγ) production during respiratory syncytial virus (RSV) is associated with prolonged viral clearance and increased disease severity in neonatal mice and humans. Alveolar macrophages (AMs) play an important role in establishing these initial conditions through cytokine production, recruitment of lymphocytes, and antimicrobial activity. These functions vary significantly in neonates compared to older children and adults and are often further influenced by invading pathogens. By regulating the cytokine environment through early, in vivo delivery of IFNγ, studies in neonatal models of murine leukemia virus have shown that immune responses can be shifted to a Type I pathway with enhanced viral clearance [12]
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