Alpha/Beta Interferon Receptor Signaling Amplifies Early Proinflammatory Cytokine Production in the Lung during Respiratory Syncytial Virus Infection

Goritzka, Michelle; Durant, Lydia; Pereira, Catherine; Salek‐Ardakani, Samira; Openshaw, Peter; Johansson, Cecilia

doi:10.1128/jvi.00333-14

Cited by 125 publications

(164 citation statements)

References 48 publications

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“…Recent studies have shown that RSV infection of IFNAR-deficient mice leads to lower levels of inflammatory cytokines (52)(53)(54), and our data show that, similarly, IFNAR Ϫ/Ϫ mice infected with HMPV have fewer inflammatory cytokine transcripts. Histological analysis of infected animals showed significantly less lung inflammation in IFNAR Ϫ/Ϫ mice than in WT mice, and IFNAR Ϫ/Ϫ mice had significantly less lung dysfunction and weight loss during infection, suggesting that IFNAR signaling contributes substantially to the major disease symptoms associated with HMPV infection (1,9,55).…”

Section: Discussionsupporting

confidence: 60%

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Hastings

Erickson

Schuster

et al. 2015

J Virol

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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...

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Section: Discussionsupporting

confidence: 60%

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Hastings

Erickson

Schuster

et al. 2015

J Virol

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“…The comparable RSV‐induced expression of Siglec‐1 on newborn and adult monocytes suggests a viral‐induced pathway that is already functional at birth. RSV‐induced expression of Siglec‐1 may be present on recruited monocytes and/or resident macrophages to regulate T cell functionality at the site of infection 9.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition or inadequate activation of T cells resulting in lower secretion of IFN‐γ may explain this high rate of reinfections 7, 8. Monocytes and T cells are both recruited to the site of RSV infection and the role of monocytes in the pathogenesis of RSV infections has been appreciated for decades 9, 10, 11, 12, 13, 14, 15. RSV increases the expression of major histocompatibility complex (MHC) molecules on monocytes, activates CD4 + T cells and induces the production of IFN‐γ by human immune cells In vitro 15.…”

Section: Introductionmentioning

confidence: 99%

Siglec‐1 inhibits RSV‐induced interferon gamma production by adult T cells in contrast to newborn T cells

et al. 2018

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Interferon gamma (IFN‐γ) plays an important role in the antiviral immune response during respiratory syncytial virus (RSV) infections. Monocytes and T cells are recruited to the site of RSV infection, but it is unclear whether cell‐cell interactions between monocytes and T cells regulate IFN‐γ production. In this study, micro‐array data identified the upregulation of sialic acid‐binding immunoglobulin‐type lectin 1 (Siglec‐1) in human RSV‐infected infants. In vitro, RSV increased expression of Siglec‐1 on healthy newborn and adult monocytes. RSV‐induced Siglec‐1 on monocytes inhibited IFN‐γ production by adult CD4+ T cells. In contrast, IFN‐γ production by RSV in newborns was not affected by Siglec‐1. The ligand for Siglec‐1, CD43, is highly expressed on adult CD4+ T cells compared to newborns. Our data show that Siglec‐1 reduces IFN‐γ release by adult T cells possibly by binding to the highly expressed CD43. The Siglec‐1‐dependent inhibition of IFN‐γ in adults and the low expression of CD43 on newborn T cells provides a better understanding of the immune response against RSV in early life and adulthood.

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“…When delivered to the lung, type I IFN in the lung was protective from C. burnetii infection in all tissues assessed, suggesting a tissue-specific response for the cytokine. Similarly, type I IFN promotes inflammatory responses in the respiratory tract following respiratory syncytial virus (RSV) infection (43). In contrast, during influenza virus infection, type I IFN decreased proinflammatory cytokines, which was directly linked to robust IL-10 expression.…”

Section: Figmentioning

confidence: 99%

Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue

et al. 2016

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Coxiella burnetii is an intracellular pathogen and the cause of Q fever. Gamma interferon (IFN-␥) is critical for host protection from infection, but a role for type I IFN in C. burnetii infection has not been determined. Type I IFN supports host protection from a related pathogen, Legionella pneumophila, and we hypothesized that it would be similarly protective in C. burnetii infection. In contrast to our prediction, IFN-␣ receptor-deficient (IFNAR ؊/؊ ) mice were protected from C. burnetii-induced infection. Therefore, the role of type I IFN in C. burnetii infection was distinct from that in L. pneumophila. Mice treated with a double-stranded-RNA mimetic were protected from C. burnetii-induced weight loss through an IFNAR-independent pathway. We next treated mice with recombinant IFN-␣ (rIFN-␣). When rIFN-␣ was injected by the intraperitoneal route during infection, disease-induced weight loss was exacerbated. Mice that received rIFN-␣ by this route had dampened interleukin 1␤ (IL-1␤) expression in bronchoalveolar lavage fluids. However, when rIFN-␣ was delivered to the lung, bacterial replication was decreased in all tissues. Thus, the presence of type I IFN in the lung protected from infection, but when delivered to the periphery, type I IFN enhanced disease, potentially by dampening inflammatory cytokines. To better characterize the capacity for type I IFN induction by C. burnetii, we assessed expression of IFN-␤ transcripts by human macrophages following stimulation with lipopolysaccharide (LPS) from C. burnetii. Understanding innate responses in C. burnetii infection will support the discovery of novel therapies that may be alternative or complementary to the current antibiotic treatment.

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Alpha/Beta Interferon Receptor Signaling Amplifies Early Proinflammatory Cytokine Production in the Lung during Respiratory Syncytial Virus Infection

Cited by 125 publications

References 48 publications

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Siglec‐1 inhibits RSV‐induced interferon gamma production by adult T cells in contrast to newborn T cells

Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue

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