Role for Innate IFNs in Determining Respiratory Syncytial Virus Immunopathology

Johnson, Teresa R.; Mertz, Sara; Gitiban, Negin; Hammond, Sue; LeGallo, Robin D.; Durbin, Russell K.; Durbin, Joan E.

doi:10.4049/jimmunol.174.11.7234

Cited by 65 publications

(68 citation statements)

References 50 publications

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“…At either time point, vvF-immunized mice harbored less virus than mice undergoing a primary RSV infection. Our plaque assay data support previous work with IFN-␥ receptor-deficient mice on the 129SvEv background showing that viral clearance after primary infection is not dependent upon IFN-␥ signaling (5,24). These data indicate that IFN-␥ deficiency does not alter viral clearance and suggest that viral load would be reduced upon inclusion of the F protein in future RSV vaccines.…”

Section: Vol 82 2008 Role Of Ifn-␥ During Rsv Vaccine-enhanced Disesupporting

confidence: 80%

Differential Role of Gamma Interferon in Inhibiting Pulmonary Eosinophilia and Exacerbating Systemic Disease in Fusion Protein-Immunized Mice Undergoing Challenge Infection with Respiratory Syncytial Virus

Castilow

Olson

Meyerholz

et al. 2008

J Virol

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Section: Vol 82 2008 Role Of Ifn-␥ During Rsv Vaccine-enhanced Disesupporting

confidence: 80%

Differential Role of Gamma Interferon in Inhibiting Pulmonary Eosinophilia and Exacerbating Systemic Disease in Fusion Protein-Immunized Mice Undergoing Challenge Infection with Respiratory Syncytial Virus

Castilow

Olson

Meyerholz

et al. 2008

J Virol

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“…These data demonstrate that IFNAR signaling contributes to the limitation of both the replication and the spread of HMPV, similar to what has been observed in related viruses (47)(48)(49)(50). One group found that both type I and II IFNs are important for RSV in BALB/c mice (50,51).…”

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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“…6C). IL-13 was chosen as an indicator of Th2 cytokine production, as this cytokine was previously found to predominate following RSV infection in STAT1 Ϫ/Ϫ mice, which lack the ability to generate a Th1 response (33). As observed in the lung samples taken at 4 days postchallenge, IFN-␥ production by splenocytes derived from mice previously infected with RSV was not significantly enhanced compared to cultures from mock-immunized animals.…”

Section: Vol 80 2006 Recombinant Ndv As a Vaccine Vector For Rsv 1133mentioning

confidence: 81%

Protection against Respiratory Syncytial Virus by a Recombinant Newcastle Disease Virus Vector

Martínez-Sobrido

Gitiban

Fernández-Sesma

et al. 2006

J Virol

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114

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Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infants and the elderly, but no safe and effective RSV vaccine is yet available. For reasons that are not well understood, RSV is only weakly immunogenic, and reinfection occurs throughout life. This has complicated the search for an effective live attenuated viral vaccine, and past trials with inactivated virus preparations have led to enhanced immunopathology following natural infection. We have tested the hypothesis that weak stimulation of innate immunity by RSV correlates with ineffective adaptive responses by asking whether expression of the fusion glycoprotein of RSV by Newcastle disease virus (NDV) would stimulate a more robust immune response to RSV than primary RSV infection. NDV is a potent inducer of both alpha/beta interferon (IFN-␣/␤) production and dendritic cell maturation, while RSV is not. When a recombinant NDV expressing the RSV fusion glycoprotein was administered to BALB/c mice, they were protected from RSV challenge, and this protection correlated with a robust anti-F CD8 ؉ T-cell response. The effectiveness of this vaccine construct reflects the differential abilities of NDV and RSV to promote dendritic cell maturation and is retained even in the absence of a functional IFN-␣/␤ receptor. Respiratory syncytial virus (RSV), a Pneumovirus of the familyParamyxoviridae, infects the majority of individuals in their first year of life. RSV is the major cause of bronchiolitis and pneumonia in infants and young children and accounts for approximately 85,000 pediatric hospitalizations per year in the United States alone (48). Many pediatric viral diseases have been eradicated or lessened in severity by successful vaccination programs, but no safe and effective vaccine yet exists for RSV despite exploitation of multiple approaches (12, 13). Difficulties in RSV vaccine development relate to (i) the poor immunogenicity of RSV (reinfection occurs throughout life [26]) and (ii) the ability of viral proteins to elicit a Th2, or allergic-type, memory response in some contexts (23,28,32,46,61). Although primary infection with RSV promotes Th1 cell differentiation, early trials of an inactivated viral vaccine (FI-RSV) led to incomplete immunity and exacerbated eosinophilic disease in vaccinated children after natural infection (10,16,35,36). These results have led RSV researchers to proceed with caution and to look beyond conventional methods and adjuvants in exploring new RSV vaccine strategies (27,45).We have hypothesized that poor stimulation of innate immune defenses by RSV might be the basis for the inadequate adaptive immune response to this infection.

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Role for Innate IFNs in Determining Respiratory Syncytial Virus Immunopathology

Cited by 65 publications

References 50 publications

Differential Role of Gamma Interferon in Inhibiting Pulmonary Eosinophilia and Exacerbating Systemic Disease in Fusion Protein-Immunized Mice Undergoing Challenge Infection with Respiratory Syncytial Virus

Differential Role of Gamma Interferon in Inhibiting Pulmonary Eosinophilia and Exacerbating Systemic Disease in Fusion Protein-Immunized Mice Undergoing Challenge Infection with Respiratory Syncytial Virus

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

Protection against Respiratory Syncytial Virus by a Recombinant Newcastle Disease Virus Vector

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