Function and Modulation of Type I Interferons during Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory infections in infants and young children, accounting for an estimated 3 million hospitalizations annually worldwide. Despite the major health burden, there is currently no licensed RSV vaccine. RSV is recognized by a range of cellular receptors including both toll-like receptors (TLR) and retinoic acid-inducible gene-I-like receptors (RIG-I). This interaction initiates signaling through mitochondrial antiviral signaling (MAVS) and interferon regulatory factor (IRF) proteins, resulting in the induction of type I interferons (IFN). Early viral control is mediated by either IFN-α or IFN-β signaling through the IFN receptor (IFNAR), inducing the production of antiviral interferon-stimulating genes (ISGs). Type I IFNs also initiate the early production of proinflammatory cytokines including interleukin 6 (IL-6), tumor necrosis factor (TNF), and IFN-γ. Type I IFN levels correlate with age, and inadequate production may be a critical factor in facilitating the increased RSV disease severity observed in infants. Here, we review the current literature on the function of type I IFNs in RSV pathogenesis, as well as their involvement in the differential immune responses observed in infants and adults.

Regulatory B Lymphocytes Colonize the Respiratory Tract of Neonatal Mice and Modulate Immune Responses of Alveolar Macrophages to RSV Infection in IL-10-Dependant Manner

“…Thus, between 6 and 14 days of life, mice become capable to control the viral replication at early d.p.i. and developed an anti-viral response confirming an age-dependent production of IFN-I upon RSV infection [8][9][10].…”

“…Therefore, we postulated that CD5 + nBreg-derived IL-10 could be responsible for the limited IFN-I in neonates. Different innate cell populations, such as pDCs, DCs, or AMs, are able to mount an anti-viral response following RSV infection and produce IFN-I [10,11]. Both pDCs and DCs are poorly represented in neonatal lungs [8,9] whereas AMs, which have been identified as the main source of IFN-I upon RSV infection in adult mice, have already fully colonized the alveolar space in 6 day-old neonates [29].…”

“…It has been demonstrated in transgenic adult Ifna6 gfp/+ mice that AMs are the major source of IFN-I in response to RSV infection [12]. Since the neonatal IFN-I response to RSV infection is barely detectable in vivo [8][9][10], we postulated that AMs in a lung-neonatal context are not able to mount a potent IFN-I response to RSV infection. To address this issue, primary AMs isolated from BAL of 6 day-old or adult BALB/c mice were infected in vitro with RSV and the IFN-I and inflammatory responses were evaluated both by qRT-PCR on cell lysates and luminex assays in supernatants.…”

“…Indeed, mice infected with RSV before seven days of life showed more severe weight loss, recruitment of inflammatory cells (eosinophils and neutrophils), and increased IL-4 production during reinfection in adulthood [7]. Moreover, RSV-infected neonatal mice have significant deficiencies in the pulmonary mobilization of antigen-presenting cells, dendritic cells (DCs), as well as in the production of type-I interferons (IFN-I) with antiviral properties [8][9][10][11]. Several publications have suggested an inadequate IFN-I production by DCs and demonstrated the impact of defective IFN-I response on the type-2-biased immunopathology to RSV infection and on the increased disease severity observed in neonates [8][9][10][11].…”

“…Moreover, RSV-infected neonatal mice have significant deficiencies in the pulmonary mobilization of antigen-presenting cells, dendritic cells (DCs), as well as in the production of type-I interferons (IFN-I) with antiviral properties [8][9][10][11]. Several publications have suggested an inadequate IFN-I production by DCs and demonstrated the impact of defective IFN-I response on the type-2-biased immunopathology to RSV infection and on the increased disease severity observed in neonates [8][9][10][11]. Conventional DCs (cDCs) and plasmacytoid DCs (pDCs) are not the only source of IFN-I since it has recently been shown in adult mice that alveolar macrophages (AMs) constitute the major source of IFN-I upon RSV infection [12].…”