Role of type I interferon signaling in human metapneumovirus pathogenesis and control of viral replication
DOI: 10.1128/JVI.03275-14; PMCID: PMC4442394
© 2015, American Society for Microbiology. 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-L1low dendritic cells (DCs), but not PD-L1high 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.
Journal of Virology
Hastings, A. K., Erickson, J. J., Schuster, J. E., Boyd, K. L., Tollefson, S. J., Johnson, M., Gilchuk, P., Joyce, S., Williams, J. V. Role of type I interferon signaling in human metapneumovirus pathogenesis and control of viral replication Journal of Virology 89, 4405-4420 (2015).