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. IMPORTANCE 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. H uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory infection (LRI), with infants and elderly and immunocompromised persons at the highest risk of severe complications from viral infection (1-9). No licensed therapeutics or vaccines exist to combat or prevent HMPV infection. Nearly all individuals have been exposed to HMPV by the age of 5 years (10, 11). Infection with this virus results in a neutralizing antibody (n...

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…151 In fact, hMPV infected-IFNAR¡/¡ mice had a higher peak of early viral replication, less airway dysfunction and lung inflammation, but cleared the virus with the same kinetics as observed in WT mice. 151 Likewise, CD8 C T cells from IFNRA¡/¡ mice expressed similar levels of PD-L1 when compare with CD8 C T cells from WT mice. However, these cells showed an upregulation of the inhibitory receptor TIM-3, thus impairing the CD8 C T cell function.…”

“…However, these cells showed an upregulation of the inhibitory receptor TIM-3, thus impairing the CD8 C T cell function. 151 Additionally, CD8 C T cells can be impaired by hMPV in a PD-1 dependent manner, similar to hRSV, as lung CD8 C T cells are impaired in HLA B7.2 transgenic (B7tg) mice and had upregulated PD-1. 152 Conversely, blocking of PD-1 by administration of monoclonal specific antibodies in B7tg mice prevented the CD8 C T cells impairment.…”

CD8 + T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection

“…WT mice treated with IFNAR-blocking antibody or mice genetically deficient in IFNAR are currently popular animal models for investigating the immune response and pathogenesis of ZIKV infection (5, 6), although two papers reported recently that CD8 ϩ T cells could be activated by ZIKV infection in B6 WT mice (8,9). Numerous studies have demonstrated that type I interferon (IFN) deficiency impaired the CD8 ϩ T cell response during virus infection through many cellular and molecule mechanisms, such as by impairing the priming effect of dendritic cells and upregulating the expression of the inhibitory molecules PD-1 and Tim3 of CD8 ϩ T cells during virus infection (10,12,13). In addition, because of the deficiency of innate immune components, the IFNAR knockout (KO) mouse model could exclude a comprehensive study of the immune response (14,15) and did not reflect the natural immune response after infection.…”

Human Interferon Alpha2a as Anti Hepatitis B and C

“…IFNAR-2c has an important role in ligand binding and signal transduction process, while IFNAR-2a and 2b are competitive inhibitors that prevent IFNα binding into IFNAR-2c. 3,4 hIFNα2 is produced by leukocytes and consists of 16 types. hIFNα2a, as one of hIFNα2 member, is widely known to have a very broad biological activity as antiviral, antiproliferative, and immunomodulative therapeutic.…”