Alveolar macrophages support interferon gamma-mediated viral clearance in RSV-infected neonatal mice

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.

Siglec‐1 inhibits RSV‐induced interferon gamma production by adult T cells in contrast to newborn T cells

“…The high rate of reinfections by RSV results in a significant burden on health care in infants and elderly 2. Interferon gamma (IFN‐γ) and T cells are essential to mount an adequate immune response during RSV infections in newborn and adult mice 3, 4, 5. This suggests an important role for IFN‐γ in the clearance of primary infections as well as in reinfections 4, 6.…”

“…Interferon gamma (IFN‐γ) and T cells are essential to mount an adequate immune response during RSV infections in newborn and adult mice 3, 4, 5. This suggests an important role for IFN‐γ in the clearance of primary infections as well as in reinfections 4, 6. Inhibition or inadequate activation of T cells resulting in lower secretion of IFN‐γ may explain this high rate of reinfections 7, 8.…”

Purified Streptococcus pneumoniae Endopeptidase O (PepO) Enhances Particle Uptake by Macrophages in a Toll-Like Receptor 2- and miR-155-Dependent Manner

“…Alveolar macrophages are important players in the pulmonary immune system (3)(4)(5)(6)(7)(8). During pneumococcal infection, clearance of pneumococci is initiated by macrophages, not neutrophils.…”

Protective role of Indoleamine 2,3 dioxygenase in Respiratory Syncytial Virus associated immune response in airway epithelial cells

“…This reduction was associated with the upregulation of antiviral proteins, such as IFIT1and Mx1 [34]. High levels of IFN-γ exposure prior to RSV infection have also been shown to inhibit RSV replication in adult BALB/c mice [35]. Though IFN-γ is largely considered a proinflammatory cytokine [36] it has also been reported to have anti-inflammatory effects [37,38,39].…”