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: We further determined the effect of RSV infection on inflammatory cell recruitment to the lungs and extravasation into the airways. The recruitment of polymorphonuclear phagocytes, which occurs early after infection, was largely independent of MAVS as similar proportions and numbers of neutrophils were present in bronchoalveolar lavages (BALs; a representation of the airways) and lung cell suspensions from infected MAVS-sufficient and -deficient mice (Fig. 4, D and E). Consistent with this notion, substantial expression of the neutrophil chemoattractant Cxcl1 was detected early after infection in both WT and Mavs−/− mice even though levels were higher in the former group (Fig. 4 F). Similarly, Cxcl1 induction and unimpaired neutrophil recruitment was also observed in IFNAR1-deficient mice infected with RSV (Goritzka et al., 2014). The recruitment of T cells, including RSV-specific CD8+ T cells, detected at day 8 p.i., also did not differ between WT and Mavs−/− mice (Fig. 4, G–I; Bhoj et al., 2008; Demoor et al., 2012). In contrast, we noticed a large difference between WT and Mavs−/− mice in lung accumulation of CD64hi inflammatory cells after RSV infection. In WT mice, leukocytes positive for CD64 and CD11b represented ∼40% of the total leukocyte population at day 2 p.i., but those cells were completely absent in lungs of Mavs−/− mice at all time points (Fig. 5, A and B). Thus, MAVS deficiency results in a general impairment of inflammatory cytokine production and absence of CD64hi inflammatory cells in the lungs after RSV infection, but does not impact neutrophil or T cell recruitment.
Affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.