9 research outputs found

    Influenza infection improves adaptive immune responses in SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice.

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    <p>(<b>A</b>) Numbers of airway CD4<sup>+</sup> T cells, (<b>B</b>) CD8<sup>+</sup> T cells, and (<b>C</b>) BALF H1N1-specific IgM and IgG levels in C57BL/6 WT, IFN-Ξ³<sup>βˆ’/βˆ’</sup> and SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice after 50 PFU PR8 infection (4 mice/group). In (A&B), <i>P</i><0.001, ANOVA; *<i>P</i><0.05, **, <i>P</i><0.01, ***, <i>P</i><0.001, Tukey's multiple comparisons test. The data for each time point were repeated in at least two independent experiments.</p

    Expression of Suppressor of Cytokine Signaling 1 (SOCS1) Impairs Viral Clearance and Exacerbates Lung Injury during Influenza Infection

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    <div><p>Suppressor of cytokine signaling (SOCS) proteins are inducible feedback inhibitors of cytokine signaling. SOCS1<sup>βˆ’/βˆ’</sup> mice die within three weeks postnatally due to IFN-Ξ³-induced hyperinflammation. Since it is well established that IFN-Ξ³ is dispensable for protection against influenza infection, we generated SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice to determine whether SOCS1 regulates antiviral immunity in vivo. Here we show that SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice exhibited significantly enhanced resistance to influenza infection, as evidenced by improved viral clearance, attenuated acute lung damage, and consequently increased survival rates compared to either IFN-Ξ³<sup>βˆ’/βˆ’</sup> or WT animals. Enhanced viral clearance in SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice coincided with a rapid onset of adaptive immune responses during acute infection, while their reduced lung injury was associated with decreased inflammatory cell infiltration at the resolution phase of infection. We further determined the contribution of SOCS1-deficient T cells to antiviral immunity. Anti-CD4 antibody treatment of SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice had no significant effect on their enhanced resistance to influenza infection, while CD8<sup>+</sup> splenocytes from SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice were sufficient to rescue RAG1<sup>βˆ’/βˆ’</sup> animals from an otherwise lethal infection. Surprisingly, despite their markedly reduced viral burdens, RAG1<sup>βˆ’/βˆ’</sup> mice reconstituted with SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> adaptive immune cells failed to ameliorate influenza-induced lung injury. In conclusion, in the absence of IFN-Ξ³, the cytoplasmic protein SOCS1 not only inhibits adaptive antiviral immune responses but also exacerbates inflammatory lung damage. Importantly, these detrimental effects of SOCS1 are conveyed through discrete cell populations. Specifically, while SOCS1 expression in adaptive immune cells is sufficient to inhibit antiviral immunity, SOCS1 in innate/stromal cells is responsible for aggravated lung injury.</p></div

    Airway cytokine responses after influenza infection.

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    <p>Levels of IFN-Ξ³, IL-6, IL-10, TNF-Ξ±, IL-1Ξ², IL-17, IL-4, IL-5 and IL-13 in BALF of C57BL/6 WT, IFN-Ξ³<sup>βˆ’/βˆ’</sup> and SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice after 50 PFU PR8 infection (4 mice/group). <i>P</i><0.001, ANOVA; *<i>P</i><0.05, **, <i>P</i><0.01, ***, <i>P</i><0.001 relative to WT and IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice, Tukey's multiple comparisons test. The data for each time point were repeated in at least two independent experiments.</p

    CD8<sup>+</sup> T cells from SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice protect against influenza infection.

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    <p>(<b>A</b>) Survival, (<b>B</b>) viral burdens, and (<b>C</b>) albumin levels (5–7 mice/group) at 11 dpi in C57BL/6 RAG1<sup>βˆ’/βˆ’</sup> mice after i.n. infection of 50 PFU PR8 influenza virus. Mice were i.p injected with 10<sup>7</sup> CD8<sup>+</sup> T cells isolated from WT, IFN-Ξ³<sup>βˆ’/βˆ’</sup> or SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice 10 days before infection. In (B&C), <i>P</i><0.01, ANOVA; *<i>P</i><0.05, **, <i>P</i><0.01, Tukey's multiple comparisons test. Data in (A&B) were combined from two independent experiments. Data in (C) are representative of two experiments.</p

    Decreased accumulation of inflammatory cells in SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice at the resolution phase of influenza infection.

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    <p>(<b>A</b>) Numbers of CD11b<sup>+</sup>, CD11b<sup>+</sup>Ly6B<sup>βˆ’</sup> and CD11b<sup>+</sup>Ly6B<sup>+</sup> myeloid cell subsets, (<b>B</b>) flow cytometry analysis of airway CD11b<sup>+</sup>, CD11b<sup>+</sup>Ly6B<sup>βˆ’</sup> and CD11b<sup>+</sup>Ly6B<sup>+</sup> myeloid cell subsets, and (<b>C</b>) numbers of CD11b<sup>+</sup>Ly6B<sup>+</sup>Ly6G<sup>+</sup> neutrophils and CD11b<sup>+</sup>Ly6B<sup>+</sup>Ly6G<sup>βˆ’</sup>Ly6C<sup>+</sup> inflammatory monocytes at 11 dpi in C57BL/6 WT, IFN-Ξ³<sup>βˆ’/βˆ’</sup> and SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice after 50 PFU PR8 infection (4 mice/group). In (A), <i>P</i><0.001, ANOVA; <i>P</i><0.05, and **, <i>P</i><0.01, and ***, <i>P</i><0.001, Tukey's multiple comparisons test, the data for each time point were repeated in at least two independent experiments. Data in (B&C) are representative of at least two experiments.</p

    Antiviral immune responses in CD4<sup>+</sup> T cell depleted mice.

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    <p>(<b>A</b>) Viral titers (4–6 mice/group), (<b>B</b>) albumin levels (4 mice/group), and (<b>C</b>) H1N1-specific IgM and IgG levels (4–6 mice/group) in C57BL/6 IFN-Ξ³<sup>βˆ’/βˆ’</sup> and SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> airways after i.n. infection of 50 PFU PR8 influenza virus. Mice were injected i.p. with GK1.5 (anti-CD4) to deplete CD4<sup>+</sup> T cells. Control mice were treated with rat IgG. In (A), <i>P</i><0.001, ANOVA; *<i>P</i><0.05, **, <i>P</i><0.01, ***, <i>P</i><0.001, Tukey's multiple comparisons test, the data for each time point were repeated in at least two independent experiments. In (B), *<i>P</i><0.05, <i>t</i> test. Data in (B&C) are representative of two independent experiments.</p

    SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice are more resistant to influenza infection.

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    <p>(<b>A</b>) Viral titers (6–9 mice/group), (<b>B</b>) albumin levels (4 mice/group), and (<b>C</b>) survival of C57BL/6 WT, IFN-Ξ³<sup>βˆ’/βˆ’</sup>, and SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice after i.n. infection of (<b>A, B</b>) 50 PFU or (<b>C</b>) 10<sup>3</sup> PFU PR8 virus. In (A&B), <i>P</i><0.001, ANOVA; *<i>P</i><0.05, **, <i>P</i><0.01, ***, <i>P</i><0.001, Tukey's multiple comparisons test. Data in (A) were combined from two independent experiments. Data in (B&C) are representative of at least two experiments.</p

    Influenza infection enhances DC recruitment in SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice.

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    <p>(<b>A</b>) Numbers of BALF cells (4 mice/group) and (<b>B</b>) flow cytometry analysis of airway CD11c<sup>+</sup> cell subsets at 7 dpi in C57BL/6 WT, IFN-Ξ³<sup>βˆ’/βˆ’</sup> and SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice after 50 PFU PR8 infection (3–4 mice/group). In (A) <i>P</i><0.001, ANOVA; *<i>P</i><0.05, ***, <i>P</i><0.001 relative to WT and IFN-Ξ³<sup>βˆ’/βˆ’</sup> mice, Tukey's multiple comparisons test, the data for each time point were repeated in at least two independent experiments. Data in (B) are representative of two independent experiments.</p

    Antiviral immune responses in RAG1<sup>βˆ’/βˆ’</sup> mice reconstituted with SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> adaptive immune cells.

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    <p>(<b>A</b>) Airway viral burdens (5–6 mice/group), (<b>B</b>) T cell numbers at 7 dpi (4–5 mice/group), (<b>C</b>) H1N1-specific antibody responses (4–6 mice/group), (<b>D</b>) cytokine responses (5–6 mice/group) at 7 dpi, and (<b>E</b>) albumin levels (5–6 mice/group) at 11 dpi in C57BL/6 RAG1<sup>βˆ’/βˆ’</sup> mice after i.n. infection of 50 PFU PR8 influenza virus. Mice were i.p injected with 2Γ—10<sup>7</sup> IFN-Ξ³<sup>βˆ’/βˆ’</sup> or SOCS1<sup>βˆ’/βˆ’</sup>IFN-Ξ³<sup>βˆ’/βˆ’</sup> splenocytes 10 weeks before influenza infection. In (A), <i>P</i><0.001, ANOVA; ***, <i>P</i><0.001, Tukey's multiple comparisons test. In (B), ***, <i>P</i><0.001, <i>t</i> test. In (C), <i>P</i><0.01, ANOVA; *<i>P</i><0.05, **, <i>P</i><0.01, Tukey's multiple comparisons test. The data for each time point were repeated in at least two independent experiments.</p
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