title: Role of type I interferon signaling in human metapneumovirus pathogenesis and control of viral replication.
abstract: Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), 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 the 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 the CD8(+) T cell response. HMPV-infected IFNAR(-/-) mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR(-/-) mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8(+) T cells of IFNAR(-/-) mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8(+) T cells of IFNAR(-/-) mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1(low) 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.
  
  
  OBJECTIVE
  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 responses to HMPV by 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.
authors: Departments of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Andrew K
authors: AK
authors: Hastings
authors: Departments of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: John J
authors: JJ
authors: Erickson
authors: Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri, USA.
authors: Jennifer E
authors: JE
authors: Schuster
authors: Departments of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Kelli L
authors: KL
authors: Boyd
authors: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Sharon J
authors: SJ
authors: Tollefson
authors: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Monika
authors: M
authors: Johnson
authors: Departments of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Pavlo
authors: P
authors: Gilchuk
authors: Departments of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Sebastian
authors: S
authors: Joyce
authors: Departments of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA john.williams@vanderbilt.edu.
authors: John V
authors: http://orcid.org/0000-0001-8377-5175
authors: JV
authors: Williams
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D029121:Metapneumovirus / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010092:Oximetry; D018184:Paramyxoviridae Infections / Q000276:immunology* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D011991:Receptors, Virus / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014779:Virus Replication / Q000502:physiology*
chemical_list: C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D007370:Interferon Type I; D011991:Receptors, Virus
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