Innate immune recognition and control of adaptive immune responses to respiratory syncytial virus infection

Abstract

Respiratory syncytial virus (RSV) is the leading cause of respiratory viral infection in infants and children, yet little is known about the natural antiviral response to RSV. We identified the signalling pathway activated by RSV that induces type I interferon production and T cell priming, and we spatiotemporally tracked the cellular source and major producer of interferon-β using interferon-β/YFP reporter mice. We then analysed the in vitro and in vivo patterns of interferon production by flow cytometry in RSV-stimulated bone marrow cells and RSV-infected lung cells. Results from in vitro analysis of RSV-stimulated bone marrow cells revealed that RSV induces interferon-β production in plasmacytoid dendritic cells, monocytes, and neutrophils. Spatial and kinetic analysis of interferon-β-producing cells in in vivo RSV-infected lung cells indicated that monocytes are rapidly recruited to the inflamed lung during the early phase of infection. These cells produced interferon-β via the MyD88-mediated, rather than the MAVS-mediated, pathway. In addition, monocyte-ablated mice exhibited decreased interferon-γ-producing CD8+ T cell frequencies. Collectively, these data indicate that monocytes play pivotal roles in cytotoxic T cell responses and are the major type I interferon producers during RSV infection. Alveolar macrophages (AMs) play a crucial role in combatting airborne pathogens, strongly express CD169, and are localized in the lung alveoli. Therefore, we used CD169-diphtheria toxin receptor (DTR) transgenic mice to explore the roles of CD169+ cells in immune responses to mucosal RSV infection. The administration of diphtheria toxin to CD169-DTR mice induced specific AM depletion and reduced the recruitment of Ly6Chi monocytes. Notably, CD169+ cell depletion reduced levels of innate cytokines, such as IFN-β, IL-6, and TNF-α, in bronchoalveolar lavage fluid during RSV infection without affecting the production of proinflammatory chemokines. Moreover, the depletion of CD169+ cells increased the recruitment of inflammatory cells to the lung during the early stage of RSV infection, although not during the later stages of RSV infection. Furthermore, the depletion of CD169+ cells reduced the recruitment of effector CD8+ T cells to the lungs after RSV mucosal infection. Our findings suggest that modulating the number of CD169+ cells to enhance immune responses to RSV infection may be useful as a new therapeutic strategy.