Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes.
Bottom Line: AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)-coupled retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV.Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN-mediated antiviral activity.Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation.
Affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.Show MeSH
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Mentions: Next we dissected the pathway leading to type I IFN induction by lung AMs. Live virus was necessary as UV-inactivated RSV administered i.n. did not elicit GFP expression (Fig. 3 A). Importantly, live virus failed to induce a GFP signal in AMs from Ifna6gfp/+ mice deficient in the RLR adaptor protein MAVS (Ifna6gfp/+ Mavs−/− mice; Fig. 3 A). This was true at all time points examined, from 8 to 96 h p.i. (Fig. 3 B), demonstrating a key role for the RLR pathway in the AM response to RSV. Consistent with that notion, primary AMs isolated from Ifna6gfp/+ mice but not from Ifna6gfp/+ Mavs−/− mice secreted large amounts of IFN-α in response to increasing doses of RSV ex vivo (Fig. 3 C). The lack of IFN-α production by Ifna6gfp/+ Mavs−/− AMs was maintained even when the cells were stimulated with RSV up to multiplicities of infection (MOIs) of 20 (not depicted).
Affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.