The type I alpha/beta interferons (IFN-␣/␤) are known to play an important role in host defense against influenza A virus infection, but we have now discovered that the recently identified type III IFNs (IFN-) constitute the major response to intranasal infection with this virus. Type III IFNs were present at much higher levels than type I IFNs in the lungs of infected mice, and the enhanced susceptibility of STAT2 ؊/؊ animals demonstrated that only signaling through the IFN-␣/␤ or IFN-pathways was sufficient to mediate protection. This finding offers a possible explanation for the similar levels of antiviral protection found in wild-type (WT) mice and in animals lacking a functional type I IFN receptor (IFNAR ؊/؊ ) but also argues that our current understanding of type III IFN induction is incomplete. While murine IFN-production is thought to depend on signaling through the type I IFN receptor, we demonstrate that intranasal influenza A virus infection leads to the robust type III IFN induction in the lungs of both WT and IFNAR ؊/؊ mice. This is consistent with previous studies showing that IFNAR-mediated protection is redundant for mucosal influenza virus infection and with data showing that the type III IFN receptor is expressed primarily by epithelial cells. However, the overlapping effects of these two cytokine families are limited by their differential receptor expression, with a requirement for IFN-␣/␤ signaling in combating systemic disease.Type I interferons (IFNs) were first recognized for their ability to interfere with influenza virus replication (31) and are now recognized as an early and powerful host defense against virus infection. In all cell types that have been investigated, virus infection results in the synthesis and secretion of the type I alpha/beta interferons (IFN-␣/␤). Once secreted, IFN-␣/␤ acts in an autocrine or paracrine manner by binding the ubiquitously expressed IFN-␣/␤ receptor (IFNAR). Receptor binding activates the Jak-STAT signaling cascade leading to transcriptional upregulation of the IFN-stimulated genes which mediate the biological effects of IFN (10,18).IFN induction by influenza A virus involves recognition of viral components by both cytoplasmic receptors and TLR7, although the precise mechanism used depends upon the infected cell type. In fibroblasts, epithelial cells, and conventional dendritic cells (cDCs), IFN-␤ gene expression is largely dependent upon virus activation of the RNA helicase retinoic acid-induced gene I (RIG-I) (26), with the subsequent phosphorylation of IFN regulatory factor 3 (IRF3) by IB kinase ε (IKKε)/TANK-binding kinase 1 (TBK1). Once IFN-␤ (as well as IFN-␣4 in mouse) has been synthesized and secreted, signaling through the Jak-STAT pathway upregulates production of IRF7, which then mediates the transcription of additional 33,45). In this way, an amplification pathway is established wherein early, IRF3-mediated production of IFN-␤ promotes the synthesis of multiple IFN-␣ subtypes.Type III IFNs were very recently discovered and are designated ...

Formalin-inactivated respiratory syncytial virus (RSV) vaccine preparations have been shown to cause enhanced disease in naive hosts following natural infection. In this study we demonstrate a similar pattern of enhanced disease severity following primary RSV infection of IFN-nonresponsive STAT1−/− mice. STAT1−/− mice showed markedly increased illness compared with wild-type BALB/c animals following RSV inoculation despite similar lung virus titers and rates of virus clearance. Histologically, STAT1−/− animals had eosinophilic and neutrophilic pulmonary infiltrates not present in wild-type or IFN-γ−/−-infected mice. In cytokine analyses of infected lung tissue, IFN-γ was induced in both STAT1−/− and wild-type mice, with preferential IL-4, IL-5, and IL-13 induction only in the STAT1−/− animals. Eotaxin was detected in the lungs of both wild-type and STAT1−/− mice following infection, with a 1.7-fold increase over wild-type in the STAT1−/− mice. Using a peptide epitope newly identified in the RSV fusion protein, we were able to demonstrate that wild-type memory CD4+ T cells stimulated by this peptide produce primarily IFN-γ, while STAT1−/−CD4+ cells produce primarily IL-13. These findings suggest that STAT1 activation by both type I (αβ) and type II (γ) IFNs plays an important role in establishing a protective, Th1 Ag-specific immune response to RSV infection.

Type I interferon (IFN) induction is an immediate response to virus infection

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infants and the elderly, but no safe and effective RSV vaccine is yet available. For reasons that are not well understood, RSV is only weakly immunogenic, and reinfection occurs throughout life. This has complicated the search for an effective live attenuated viral vaccine, and past trials with inactivated virus preparations have led to enhanced immunopathology following natural infection. We have tested the hypothesis that weak stimulation of innate immunity by RSV correlates with ineffective adaptive responses by asking whether expression of the fusion glycoprotein of RSV by Newcastle disease virus (NDV) would stimulate a more robust immune response to RSV than primary RSV infection. NDV is a potent inducer of both alpha/beta interferon (IFN-␣/␤) production and dendritic cell maturation, while RSV is not. When a recombinant NDV expressing the RSV fusion glycoprotein was administered to BALB/c mice, they were protected from RSV challenge, and this protection correlated with a robust anti-F CD8 ؉ T-cell response. The effectiveness of this vaccine construct reflects the differential abilities of NDV and RSV to promote dendritic cell maturation and is retained even in the absence of a functional IFN-␣/␤ receptor. Respiratory syncytial virus (RSV), a Pneumovirus of the familyParamyxoviridae, infects the majority of individuals in their first year of life. RSV is the major cause of bronchiolitis and pneumonia in infants and young children and accounts for approximately 85,000 pediatric hospitalizations per year in the United States alone (48). Many pediatric viral diseases have been eradicated or lessened in severity by successful vaccination programs, but no safe and effective vaccine yet exists for RSV despite exploitation of multiple approaches (12, 13). Difficulties in RSV vaccine development relate to (i) the poor immunogenicity of RSV (reinfection occurs throughout life [26]) and (ii) the ability of viral proteins to elicit a Th2, or allergic-type, memory response in some contexts (23,28,32,46,61). Although primary infection with RSV promotes Th1 cell differentiation, early trials of an inactivated viral vaccine (FI-RSV) led to incomplete immunity and exacerbated eosinophilic disease in vaccinated children after natural infection (10,16,35,36). These results have led RSV researchers to proceed with caution and to look beyond conventional methods and adjuvants in exploring new RSV vaccine strategies (27,45).We have hypothesized that poor stimulation of innate immune defenses by RSV might be the basis for the inadequate adaptive immune response to this infection.

Maternal antibodies directed to pre-F, followed by antibodies directed to G, can modulate RSV disease severity in young infants.