Type I Interferons Produced by Alveolar Macrophages are Important Drivers of Lung Inflammation During Respiratory Syncytial Virus (RSV) Infection

Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in infants. Type I interferons (IFNs) are crucial for protection from RSV. To identify the cellular source of type I IFNs following RSV infection, we utilized a mouse strain in which green fluorescent protein (GFP) is expressed under control of the Ifna6 promoter. Upon intranasal RSV infection, GFP was only detected in alveolar macrophages (AMs). We confirmed by mRNA analysis that AM are the major source of type I IFNs following RSV and showed that their response critically depend on MAVS, the adaptor protein for cytosolic RIG-I-like receptors. Like type I IFN receptor-deficient mice, MAVS-deficient mice displayed a loss of viral control that correlated with a marked deficiency in the recruitment of inflammatory monocytes. The latter could be restored by administration of CCL2 to the lungs and, surprisingly, led to nearly normal control of viral infection. Thus, AMs act as the primary initiators of immunity to RSV, secreting type I IFNs that induce the production of monocyte chemoattractants. Recruited monocytes serve as crucial and non-redundant effectors of innate resistance to RSV, indicating a hitherto unappreciated cell-extrinsic mechanism of type I IFN action in antiviral immunity.