Article

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: 5.36). 07/2005; 174(11):7234-41. DOI: 10.4049/jimmunol.174.11.7234
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Teresa R. Johnson, Jun 18, 2015
0 Followers
 · 
123 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immune responses to virus infection undergo significant change as part of the aging process. Here we examine the inflammatory responses of older, but otherwise immunologically naive mice to infection with pneumonia virus of mice (PVM). Although we see no changes in the extent or kinetics of virus replication, we observe diminished local production of inflammatory mediators, including MIP-1alpha, JE/MCP-1, IFN-gamma and IFN-gamma-induced MIG and IP-10, and interleukins (IL)-6 and IL-17. Levels of KC and IL-1alpha remained unchanged. Age-dependent diminished production of proinflammatory mediators was associated with diminished recruitment of granulocytes and reduced severity of clinical responses, including weight loss and respiratory dysfunction. The differences observed when comparing these results to those reported among elderly human subjects may be related to the specific extent of aging and its impact on biochemical and cellular inflammatory responses and/or the role of lifetime virus re-exposure on the clinical outcome from acute pneumovirus disease.
    Virology 12/2007; 368(1):182-90. DOI:10.1016/j.virol.2007.06.020 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bovine respiratory syncytial virus (BRSV) is able to counteract the alpha/beta interferon (IFN-alpha/beta)-mediated antiviral response for efficient replication in a host-specific manner. Mice models have been developed for experimental infection with human, but not bovine, respiratory syncytial virus strains. Here, it is shown that BRSV can replicate efficiently on primary cell cultures derived from type I IFN receptor-deficient, but not from wild-type IFN-competent, mice. However, BRSV infection was not enhanced in mice devoid of the type I IFN receptor. These results show that type I IFN is a major host-range determinant for infection at the cellular level, but that other factors control virus replication and pathology in vivo.
    Journal of General Virology 09/2006; 87(Pt 8):2145-8. DOI:10.1099/vir.0.82091-0 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Type I interferon receptor (IFNAR) signaling regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses including human metapneumovirus (HMPV) have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR(-/-)) mice to assess the effect of IFNAR signaling on HMPV replication and CD8(+) T cell response. HMPV-infected IFNAR(-/-) mice had a higher peak of early viral replication, but cleared virus with similar kinetics to wild-type (WT) mice. However, IFNAR(-/-) mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8(+) T cells in IFNAR(-/-) mice post-HMPV expressed similar levels of the inhibitory receptor programmed death-1 (PD-1) as WT. However, despite lower expression of the inhibitory ligand PD-L1, HMPV-specific CD8(+) T cells in IFNAR(-/-) mice were more functionally impaired than WT and upregulated the inhibitory receptor TIM-3. Analysis of the antigen presenting cell subsets in the lungs revealed that the expansion of PD-L1(lo) dendritic cells (DCs), but not PD-L1(high) alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8(+) T cell impairment. Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8(+) T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8(+) T cell impairment via PD-1:PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune response to HMPV using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8(+) T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor TIM-3 may contribute to CD8(+) T cell impairment. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 02/2015; 89(8). DOI:10.1128/JVI.03275-14 · 4.65 Impact Factor