Role for Innate IFNs in Determining Respiratory Syncytial Virus Immunopathology

Columbus Children's Research Institute and Department of Pediatrics, Ohio State University College of Medicine and Public Health, Columbus, 43205, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2005; 174(11):7234-41. DOI: 10.4049/jimmunol.174.11.7234
Source: PubMed


Respiratory syncytial virus (RSV) is the major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. The difficulties involved in RSV vaccine development were recognized in an early vaccine trial, when children immunized with a formalin-inactivated virus preparation experienced enhanced illness after natural infection. Subsequent research in animal models has shown that the vaccine-enhanced disease is mediated at least in part by memory cells producing Th2 cytokines. Previously we had observed enhanced, eosinophilic lung pathology during primary infection of IFN-deficient STAT1(-/-) mice that are incapable of generating Th1 CD4(+) cells. To determine whether these effects depended only on Th2 cytokine secretion or involved other aspects of IFN signaling, we infected a series of 129SvEv knockout mice lacking the IFN-alphabetaR (IFN-alphabetaR(-/-)), the IFN-gammaR (IFN-gammaR(-/-)), or both receptors (IFN-alphabetagammaR(-/-)). Although both the IFN-gammaR(-/-) and the IFN-alphabetagammaR(-/-) animals generated strong Th2 responses to RSV-F protein epitopes, predominantly eosinophilic lung disease was limited to mice lacking both IFNRs. Although the absolute numbers of eosinophils in BAL fluids were similar between the strains, very few CD8(+) T cells could be detected in lungs of IFN-alphabetagammaR(-/-) animals, leaving eosinophils as the predominant leukocyte. Thus, although CD4(+) Th2 cell differentiation is necessary for the development of allergic-type inflammation after infection and appears to be unaffected by type I IFNs, innate IFNs clearly have an important role in determining the nature and severity of RSV disease.

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    • "For IFN-α/β, this is expected because type I IFN production relies on a positive-feedback loop through the type I IFN receptor (26). In addition, previous studies have shown that type I IFNs play a critical role in induction of IFN-γ gene expression through the activation of STAT4 (32, 33) or increased signaling through other cytokine receptors such as IFN-γ receptor by increased levels of STAT1 (19, 34). Furthermore, since the IFN responses were reduced in IFNAR1−/− mice, this resulted in a diminished induction of ISGs as has previously been shown for TLR stimulation (35, 36) and for bone marrow-derived DCs (BMDCs) stimulated with RSV (37). "
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    ABSTRACT: Unlabelled: 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.
    Journal of Virology 03/2014; 88(11). DOI:10.1128/JVI.00333-14 · 4.44 Impact Factor
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    • "Although the initial expression of IFN proteins themselves is not affected in IFNRKO mice (22), IFN responses are not transduced, and the mice succumb to cytopathic viruses (e.g. vesicular stomatitis virus and Semliki Forest virus) at doses 106-fold less than do WT mice (21, 22, 75). Consistent with these studies, we show that mice defective in IFNR signaling maintained significantly higher systemic and CNS HIV-1 burdens than did WT mice (Fig. 2), albeit lesser in extent than that seen with some other viruses (22, 75). "
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    ABSTRACT: The roles of Type I interferon (IFN) in human immunodeficiency virus Type 1 (HIV-1) neuropathogenesis are poorly understood; both protective and deleterious effects of IFN signaling have been described. We used genetically modified mice deficient in the Type I IFN receptor (IFNRKO) to analyze the progress of HIV-1 brain infection and neuropathogenesis in the absence of IFN signaling. IFNRKO and wild-type (WT) mice on the 129xSv/Ev or C57BL/6 strain backgrounds were infected systemically with EcoHIV, a chimeric HIV-1 that productively infects mice. IFNRKO mice showed higher HIV-1 expression in spleen and peritoneal macrophages and greater virus infiltration into the brain compared to WT mice. Neuropathogenesis was studied by histopathological, immunohistochemical, immunofluorescence, and polymerase chain reaction analyses of brain tissues after the virus was inoculated into the brain by stereotaxic intracerebral injection. Both IFNRKO and WT mice showed readily detectable HIV-1 and brain lesions, including microglial activation, astrocytosis, and increased expression of genes coding for inflammatory cytokines and chemokines typical of human HIV-1 brain disease. Parameters of HIV-1 neuropathogenesis, including HIV-1 expression in microglia/macrophages, were significantly greater in IFNRKO than in WT mice. Our results show unequivocally that Type I IFN signaling and responses limit HIV-1 infection and pathogenesis in the brains of mice.
    12/2013; 73(1). DOI:10.1097/NEN.0000000000000026
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    • " immune response with high levels of IFN - γ in the lung . However , RSV infection in STAT1 knock - out ( KO ) mice of the same genetic background resulted in a mixed Th1 / Th2 response with high levels of Interleukin - 4 , Interleukin - 5 , Inter - leukin - 13 , and even higher levels of IFN - γ than seen in the WT mouse ( Durbin et al . , 2002 ; Johnson et al . , 2005 ) . RSV infection increased airway obstruction , airway hyperresponsiveness and airway epithelial mucus production in STAT1 KO mice ( Hashimoto et al . , 2005 ) , while these features were not present in RSV - infected WT mice . Others have also shown that inducing Type I IFN expression can prevent Th2 immune responses as a result of RS"
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    ABSTRACT: Human RSV causes an annual epidemic of respiratory tract illness in infants and in elderly. Mechanisms by which RSV antagonizes IFN-mediated antiviral responses include inhibition of type I IFN mRNA transcription and blocking signal transduction of JAK/STAT family members. The suppressor of cytokines signaling (SOCS) gene family utilizes a feedback loop to inhibit cytokine responses and block the activation of the JAK/STAT signaling pathway. To evaluate the potential of SOCS molecules to subvert the innate immune response to RSV infection, eight SOCS family genes were examined. RSV infection up-regulated SOCS1, SOCS3, and CIS mRNA expression in HEp-2 cells. Suppression of SOCS1, SOCS3 and CIS by short interfering ribonucleic acid (siRNA) inhibited viral replication. Furthermore, inhibition of SOCS1, SOCS3, or CIS activated type I IFN signaling by inducing STAT1/2 phosphorylation. These results suggest that RSV infection escapes the innate antiviral response by inducing SOCS1, SOCS3 or CIS expression in epithelial cells.
    Virology 08/2009; 391(2):162-70. DOI:10.1016/j.virol.2009.06.026 · 3.32 Impact Factor
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