Goritzka et al. describe a role for recruited inflammatory monocytes in antiviral immunity and protection from RSV infection in mice. The authors demonstrate that this is critically dependent on the production of type I IFNs by alveolar macrophages triggered via RIG-I–like receptors, thus highlighting an important cell-extrinsic mechanism of type I IFN–mediated antiviral activity.

Type I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFN-α/β) receptor (IFNAR) to induce genes that encode proteins important for limiting viral replication and directing immune responses. To investigate the extent to which type I IFNs play a role in the local regulation of inflammation in the airways, we examined their importance in early lung responses to infection with respiratory syncytial virus (RSV). IFNAR1-deficient (IFNAR1−/−) mice displayed increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was markedly reduced in the lungs of IFNAR1−/− mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemokines in the lungs of RSV-infected mice were also greatly reduced in the absence of IFNAR signaling. Furthermore, low levels of proinflammatory cytokines were also detected in the lungs of IFNAR1−/− mice challenged with noninfectious innate immune stimuli such as selected Toll-like receptor (TLR) agonists. Finally, recombinant IFN-α was sufficient to potentiate the production of inflammatory mediators in the lungs of wild-type mice challenged with innate immune stimuli. Thus, in addition to its well-known role in antiviral resistance, type I IFN receptor signaling acts as a central driver of early proinflammatory responses in the lung. Inhibiting the effects of type I IFNs may therefore be useful in dampening inflammation in lung diseases characterized by enhanced inflammatory cytokine production.IMPORTANCE The initial response to viral infection is characterized by the production of interferons (IFNs). One group of IFNs, the type I IFNs, are produced early upon virus infection and signal through the IFN-α/β receptor (IFNAR) to induce proteins important for limiting viral replication and directing immune responses. Here we examined the importance of type I IFNs in early responses to respiratory syncytial virus (RSV). Our data suggest that type I IFN production and IFNAR receptor signaling not only induce an antiviral state but also serve to amplify proinflammatory responses in the respiratory tract. We also confirm this conclusion in another model of acute inflammation induced by noninfectious stimuli. Our findings are of relevance to human disease, as RSV is a major cause of infant bronchiolitis and polymorphisms in the IFN system are known to impact disease severity.

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Pattern recognition receptors (PRRs) and cytokine receptors are key players in the initiation of immune responses to infection. PRRs detecting viral RNA, such as toll like receptor (TLR)-3, -7/8, and RIG-I like receptors (RLRs; RIG-I and MDA-5), as well as cytokine receptors such as interleukin 1 receptor (IL-1R), have been implicated in responses to RNA viruses that infect the airways. The latter includes respiratory syncytial virus (RSV), a human pathogen that can cause severe lower respiratory tract infections, especially in infants. To evaluate the collective contribution of PRRs and IL-1R signalling to RSV immunity, we generated Myd88/Trif/Mavs−/− mice that are deficient in signalling by all TLRs, RLRs and IL-1R, as well as other cytokine receptors such as IL-18 receptor. Early production of pro-inflammatory mediators and lung infiltration by immune cells were completely abrogated in infected Myd88/Trif/Mavs−/− mice. However, RSV-specific CD8+ T cells were elicited and recruited into the lungs and airways. Consistent with these findings, Myd88/Trif/Mavs−/− mice survived RSV infection but displayed higher viral load and weight loss. These data highlight an unappreciated level of redundancy in pathways that couple innate virus sensing to adaptive immunity, providing the host with remarkable resilience to infection.

During respiratory syncytial virus (RSV) infection CD8+ T cells both assist in viral clearance and contribute to immunopathology. CD8 + T cells recognize viral peptides presented by dendritic cells (DCs), which can directly present viral antigens when infected or, alternatively, "cross-present" antigens after endocytosis of dead or dying infected cells. Mouse CD8α + and CD103 + DCs excel at cross-presentation, in part because they express the receptor DNGR-1 that detects dead cells by binding to exposed F-actin and routes internalized cell debris into the cross-presentation pathway. As RSV causes death in infected epithelial cells, we tested whether cross-presentation via DNGR-1 is necessary for CD8 + T-cell responses to the virus. DNGR-1-deficient or wild-type mice were intranasally inoculated with RSV and the magnitude of RSV-specific CD8+ T-cell induction was measured. We found that during live RSV infection, cross-presentation via DNGR-1 did not have a major role in the generation of RSV-specific CD8+ T-cell responses. However, after intranasal immunization with dead cells infected with RSV, a dependence on DNGR-1 for RSV-specific CD8 + T-cell responses was observed, confirming the ascribed role of the receptor. Thus, direct presentation by DCs may be the major pathway initiating CD8 + T-cell responses to RSV, while DNGR-1-dependent cross-presentation has no detectable role. Keywords: CD8+ T cell r Cross-presentation r DNGR-1 r Lung infection r Virus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionRespiratory syncytial virus (RSV) is an important respiratory virus of the single-stranded RNA virus family Paramyxoviridae. RSV disease burden is estimated at 64 million cases and up to 160,000 deaths every year worldwide (www.who.int). While RSV disease manifests as a simple common cold in the majority of cases, between 2 and 3% of children develop severe bronchiolitis. Although most of these children recover, they have a greater risk of developing recurrent wheeze and asthma-like symptoms in later childhood [1,2]. RSV infection induces a robust virusCorrespondence: Dr. Cecilia Johansson e-mail: c.johansson@imperial.ac.uk specific CD8 + T-cell response. These T cells play a key role in viral clearance by destroying infected cells [3] although, in mouse models, they also contribute to lung immunopathology following RSV infection [1,4,5]. Antigen processing and presentation of peptides on MHC class I (MHC-I) is crucial for CD8 + T-cell responses to RSV and other viruses. The classical pathway, whereby peptides from the cytosol are loaded onto MHC-I molecules in the ER and transported to the cell surface, is thought to be the major mechanism by which viral antigens are displayed on the surface of infected cells [6]. However, uninfected cells can also present viral antigens in some instances. This is termed "cross-presentation" and involves antigens released from virally infected cells, often in the form of debris of lysed cells, being taken...