Control of IFN-I responses by the aminopeptidase IRAP in neonatal C57BL/6 alveolar macrophages during RSV infection

Abstract

Respiratory Syncytial Virus (RSV) is the major cause of lower respiratory tract infection in infants, in whom, the sensing of RSV by innate immune receptors and its regulation are still poorly described. However, the severe bronchiolitis following RSV infection in neonates has been associated with a defect in type I interferons (IFN-I) production, a cytokine produced mainly by alveolar macrophages (AMs) upon RSV infection in adults. In the present study, neonatal C57BL/6 AMs mobilized very weakly the IFN-I pathway upon RSV infection in vitro and failed to restrain virus replication. However, IFN-I productions by neonatal AMs were substantially increased by the deletion of Insulin-Responsive AminoPeptidase (IRAP), a protein previously involved in the regulation of IFN-I production by dendritic cells. Moreover, neonatal IRAPKO AMs showed a higher expression of IFN-stimulated genes than their wild-type C57BL/6 counterpart. Interestingly, depletion of IRAP did not affect adult AM responses. Finally, we demonstrated that newborn IRAPKO mice infected with RSV had more IFN-I in their lungs and eliminated the virus more efficiently than WT neonates. Taken together, early-life susceptibility to RSV infection may be related to an original age-dependent suppressive function of IRAP on the IFN-I driven-antiviral responses in neonatal AMs.

Severity of neonatal influenza infection is driven by type I interferon and oxidative stress

“…In contrast, we demonstrate IV induces similar IFN transcription in murine neonates compared to adults. However, consistent with others ( 41 ), previous work from our group revealed downstream IFN signaling and feedback is different in the IV-infected neonate, as ISGs are downregulated ( 33 ). Finally, IFNβ prior to infection is protective, but induces rapid death if given after IV infection.…”

“…In contrast to infected neonates, IFNβ treatment had no effect on survival of age-matched uninfected neonates ( Figure 2b , green dashed line ). Previously, we demonstrated that neonates have a delayed upregulation of interferon stimulated genes (ISG) in influenza viral infection ( 33 ) and others have demonstrated this with RSV infection ( 41 ). Surprisingly, no differences in IFNβ transcription were found between WT neonates and adults at 1- or 3-days post-infection, which suggests that neonates have an aberrant interferon stimulation pathway which increases sensitivity to IFNβ effects, compared to adults ( Supplemental Figure 1 ).…”

“…For example, respiratory syncytial virus (RSV) induces poor IFN I, specifically IFNα, which contributes to RSV-mediated immunopathogenesis ( 75 ). This reduction in IFN I during RSV is dependent on insulin-responsive aminopeptidase (IRAP) in alveolar macrophages ( 41 ) or hematopoietic growth factor ligand (Flt3-L) in DCs ( 76 ). In contrast, we demonstrate IV induces similar IFN transcription in murine neonates compared to adults.…”

Diverging patterns in innate immunity against respiratory viruses during a lifetime: lessons from the young and the old

“…Interestingly, deletion of insulin-responsive aminopeptidase (IRAP), a protein involved in regulation of IFN-I production, substantially enhanced IFN-I in neonatal alveolar macrophages, but not in adult ones. Neonatal IRAP-deficient mice infected with RSV cleared the virus more efficiently compared to wild-type mice [ 56 ]. This suggests that IRAP is an age-dependent regulator of IFN-I expression and influences protection and immunity to respiratory viruses.…”