The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice - PubMed (original) (raw)

The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice

G E Price et al. J Virol. 2000 May.

Abstract

During influenza virus infection innate and adaptive immune defenses are activated to eliminate the virus and thereby bring about recovery from illness. Both arms of the adaptive immune system, antibody neutralization of free virus and termination of intracellular virus replication by antiviral cytotoxic T cells (CTLs), play pivotal roles in virus elimination and protection from disease. Innate cytokine responses, such as alpha/beta interferon (IFN-alpha/beta) or IFN-gamma, can have roles in determining the rate of virus replication in the initial stages of infection and in shaping the initial inflammatory and downstream adaptive immune responses. The effect of these cytokines on the replication of pneumotropic influenza A virus in the respiratory tract and in the regulation of adaptive antiviral immunity was examined after intranasal infection of mice with null mutations in receptors for IFN-alpha/beta, IFN-gamma, and both IFNs. Virus titers in the lungs of mice unable to respond to IFNs were not significantly different from congenic controls for both primary and secondary infection. Likewise the mice were comparably susceptible to X31 (H3N2) influenza virus infection. No significant disruption to the development of normal antiviral CTL or antibody responses was observed. In contrast, mice bearing the disrupted IFN-alpha/beta receptor exhibited accelerated kinetics and significantly higher levels of neutralizing antibody activity during primary or secondary heterosubtypic influenza virus infection. Thus, these observations reveal no significant contribution for IFN-controlled pathways in shaping acute or memory T-cell responses to pneumotropic influenza virus infection but do indicate some role for IFN-alpha/beta in the regulation of antibody responses. Recognizing the pivotal role of CTLs and antibody in virus clearance, it is reasonable to assume a redundancy in IFN-mediated antiviral effects in pulmonary influenza. However, IFN-alpha/beta seems to be a valid factor in determining tissue tropism and replicative rates of highly virulent influenza virus strains as reported previously by others, and this aspect is discussed here.

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Figures

FIG. 1

FIG. 1

Susceptibility to influenza virus infection of mice lacking receptors for IFN-α/β, IFN-γ, or both IFNs. 129/SvEv, IFNα/βR−/−, IFNγR−/−, and IFNα/β-γR−/− mice were infected with X31, and the survival of infected mice was observed over a period of 25 days. The percent survival is shown for groups of 10 to 15 mice. Virus was administered i.n. at doses of 107 PFU (●), 106 PFU (▴), 105 PFU (▾), 104 PFU (⧫) or 102 PFU (■).

FIG. 2

FIG. 2

Kinetics of lung virus replication after primary (X31) or challenge infection with A/PR/8/34 influenza A virus in mice lacking receptors for IFN-α/β, IFN-γ, or both IFNs compared to their 129/SvEv congenic controls. Lung virus titers were measured following infection of naive (primary) IFNα/βR−/−, IFNγR−/−, IFNα/β-γR−/−, or 129/SvEv control mice with 500 PFU of X31 (left panels) or following challenge of mice which had been primed with 500 PFU of X31 30 days previously with the heterologous A/PR/8/34 influenza (500 PFU i.n.) (right panels). Lung virus titers are expressed as the mean ± the standard error of the mean (SEM) log10 TCID50/gram of lung tissue of three to five mice.

FIG. 3

FIG. 3

Virus-specific CD8+ T cells in primary and challenge influenza infection of mice lacking receptors for IFN-α/β, IFN-γ, or both IFNs compared to controls. Naive IFNα/βR−/− (A), IFNγR−/− (B), IFNα/β-γR−/− (C), or control (D) mice were infected with 500 PFU of X31, and the numbers of virus-specific CD8+ T cells in the BAL fluid were measured. BAL samples from each group of three to five mice were pooled, and the numbers of virus-specific CTLs were determined by staining CD8+ T cells for intracellular IFN-γ (left panels) or TNF-α (right panels) secretion, following stimulation of cells with NP366–374 (●) or NS2114–121 (▴) viral peptide. Alternatively, X31 primed mice (500 PFU i.n.) were challenged with A/PR/8/34 (500 PFU i.n.) 30 days later (as indicated by the arrow), and the numbers of virus-specific CD8+ T cells were determined as described above. The BAL cell counts per mouse (◊) were used, together with the flow cytometry data, to calculate the average numbers for the total CD8+ T cells specific to NP366–374 or NS2114–121 peptide epitope. BAL samples (total volume, 1 ml/lung) containing <104 cells/ml (the limit of detection of our hemocytometer counting assay) were estimated as 104 cells per lung.

FIG. 4

FIG. 4

Generation and maintenance of primary or memory virus-specific antibody responses of mice lacking receptors for IFN-α/β, IFN-γ, or both IFNs compared to controls. (A) The ability of IFNα/βR−/−, IFNγR−/−, IFNα/β-γR−/−, or 129/SvEv control mice to produce protective neutralizing antibodies was tested by measuring HI antibody titers in the sera of mice infected i.n. with 500 PFU of X31 (H3N2) (primary infection), or following their challenge on day 30 after primary infection (as indicated by the arrow), with 500 PFU of the heterologous A/PR/8/34 (H1N1) virus. The titers of X31 (●)- and A/PR/8/34 (○)-specific HI antibodies were estimated individually, and the results are expressed as the mean ± the SEM log10 HI antibody titers of groups of three to five mice. The isotype pattern of antibodies in the sera of IFNα/βR−/−, IFNγR−/−, IFNα/β-γR−/−, or 129/SvEv control mice following i.n. infection with 500 PFU of X31 was measured on days 7 and 10 after virus inoculation. (B and C) The results are shown as an ELISA titer of virus-specific antibody (mean ± the SEM log10 of three to five mice) of the IgM, IgG, or IgA isotype (B) or the IgG1, IgG2a, IgG2b, or IgG3 isotype (C).

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