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Mint3/Apba3 depletion ameliorates severe murine influenza pneumonia and macrophage cytokine production in response to the influenza virus

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ABSTRACT

Influenza virus (IFV) infection is a common cause of severe pneumonia. Studies have suggested that excessive activation of the host immune system including macrophages is responsible for the severe pathologies mediated by IFV infection. Here, we focused on the X11 protein family member Mint3/Apba3, known to promote ATP production via glycolysis by activating hypoxia inducible factor-1 (HIF-1) in macrophages, and examined its roles in lung pathogenesis and anti-viral defence upon IFV infection. Mint3-deficient mice exhibited improved influenza pneumonia with reduced inflammatory cytokines/chemokine levels and neutrophil infiltration in the IFV-infected lungs without alteration in viral burden, type-I interferon production, or acquired immunity. In macrophages, Mint3 depletion attenuated NF-κB signalling and the resultant cytokine/chemokine production in response to IFV infection by increasing IκBα and activating the cellular energy sensor AMPK, respectively. Thus, Mint3 might represent one of the likely therapeutic targets for the treatment of severe influenza pneumonia without affecting host anti-viral defence through suppressing macrophage cytokine/chemokine production.

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Mint3 deficiency does not affect the induction of type-I interferons and IFV-specific antibody production.(a) Viral copy numbers in the infected lungs. The lungs of WT and Mint3−/− mice (n = 6 per group) at day 0, 4, and 8 following infection with IFV were homogenized. Total RNA was extracted from the infected lungs and viral genome RNA copies were quantified by qPCR. (b) IFN-α and IFN-γ levels in the BALF from WT and Mint3−/− mice (n = 6 per group) after IFV infection. Data are presented as the means ± SD and are representative of three independent experiments. *P < 0.05, **P < 0.01 by the Student’s t-test. (c) IFV-specific antibody production. WT and Mint3−/− mice (n = 6 per group) were intranasally infected twice with 103 PFU of IFV on day 0 and 21. IFV-specific IgG in serum and IgA in the BALF were analysed on day 0 and 7 after the second infection. Data are presented as the means ± SD of triplicates. Data are representative of two independent experiments. *P < 0.05, **P < 0.01 by the Student’s t-test.
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f2: Mint3 deficiency does not affect the induction of type-I interferons and IFV-specific antibody production.(a) Viral copy numbers in the infected lungs. The lungs of WT and Mint3−/− mice (n = 6 per group) at day 0, 4, and 8 following infection with IFV were homogenized. Total RNA was extracted from the infected lungs and viral genome RNA copies were quantified by qPCR. (b) IFN-α and IFN-γ levels in the BALF from WT and Mint3−/− mice (n = 6 per group) after IFV infection. Data are presented as the means ± SD and are representative of three independent experiments. *P < 0.05, **P < 0.01 by the Student’s t-test. (c) IFV-specific antibody production. WT and Mint3−/− mice (n = 6 per group) were intranasally infected twice with 103 PFU of IFV on day 0 and 21. IFV-specific IgG in serum and IgA in the BALF were analysed on day 0 and 7 after the second infection. Data are presented as the means ± SD of triplicates. Data are representative of two independent experiments. *P < 0.05, **P < 0.01 by the Student’s t-test.

Mentions: Activation of innate immunity in response to IFV regulates anti-viral protective immunity31. To evaluate the impact of Mint3 deficiency on anti-IFV protection, we first analysed the viral copy number in the IFV-infected lungs of WT and Mint3−/− mice on day 0, 4, and 8 following the IFV infection. Mint3 depletion did not largely affect the viral copy number in the IFV-infected lungs (Fig. 2a). Type-I interferons (IFN-α/β) are the primary factors that induce host resistance to IFV. In particular, IFN-α induction in the late stage of IFV infection is essential for protection against IFV3132. In contrast to cytokine/chemokine production, no significant difference was observed in IFN-α production in the infected lungs between WT and Mint3−/− mice (Fig. 2b). Notably, the level of the type-II interferon IFN-γ was significantly lower in the lungs of Mint3−/− mice than in those of WT mice on day 8 but not on day 4 after infection (Fig. 2b) for unknown reasons. Next, we assessed the induction of humoral acquired immunity against IFV in Mint3−/− mice. WT and Mint3−/− mice were infected again with IFV on day 21 after the first infection (representing the second infection) and the production of virus-specific antibodies was analysed on day 7 after the second infection. Mint3 depletion in mice affected neither the production of virus-specific IgG in the serum nor virus-specific IgA in the lung mucosa (Fig. 2c). Collectively, these data suggest that Mint3 is dispensable for the induction of protective immunity against IFV infection in mice.


Mint3/Apba3 depletion ameliorates severe murine influenza pneumonia and macrophage cytokine production in response to the influenza virus
Mint3 deficiency does not affect the induction of type-I interferons and IFV-specific antibody production.(a) Viral copy numbers in the infected lungs. The lungs of WT and Mint3−/− mice (n = 6 per group) at day 0, 4, and 8 following infection with IFV were homogenized. Total RNA was extracted from the infected lungs and viral genome RNA copies were quantified by qPCR. (b) IFN-α and IFN-γ levels in the BALF from WT and Mint3−/− mice (n = 6 per group) after IFV infection. Data are presented as the means ± SD and are representative of three independent experiments. *P < 0.05, **P < 0.01 by the Student’s t-test. (c) IFV-specific antibody production. WT and Mint3−/− mice (n = 6 per group) were intranasally infected twice with 103 PFU of IFV on day 0 and 21. IFV-specific IgG in serum and IgA in the BALF were analysed on day 0 and 7 after the second infection. Data are presented as the means ± SD of triplicates. Data are representative of two independent experiments. *P < 0.05, **P < 0.01 by the Student’s t-test.
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f2: Mint3 deficiency does not affect the induction of type-I interferons and IFV-specific antibody production.(a) Viral copy numbers in the infected lungs. The lungs of WT and Mint3−/− mice (n = 6 per group) at day 0, 4, and 8 following infection with IFV were homogenized. Total RNA was extracted from the infected lungs and viral genome RNA copies were quantified by qPCR. (b) IFN-α and IFN-γ levels in the BALF from WT and Mint3−/− mice (n = 6 per group) after IFV infection. Data are presented as the means ± SD and are representative of three independent experiments. *P < 0.05, **P < 0.01 by the Student’s t-test. (c) IFV-specific antibody production. WT and Mint3−/− mice (n = 6 per group) were intranasally infected twice with 103 PFU of IFV on day 0 and 21. IFV-specific IgG in serum and IgA in the BALF were analysed on day 0 and 7 after the second infection. Data are presented as the means ± SD of triplicates. Data are representative of two independent experiments. *P < 0.05, **P < 0.01 by the Student’s t-test.
Mentions: Activation of innate immunity in response to IFV regulates anti-viral protective immunity31. To evaluate the impact of Mint3 deficiency on anti-IFV protection, we first analysed the viral copy number in the IFV-infected lungs of WT and Mint3−/− mice on day 0, 4, and 8 following the IFV infection. Mint3 depletion did not largely affect the viral copy number in the IFV-infected lungs (Fig. 2a). Type-I interferons (IFN-α/β) are the primary factors that induce host resistance to IFV. In particular, IFN-α induction in the late stage of IFV infection is essential for protection against IFV3132. In contrast to cytokine/chemokine production, no significant difference was observed in IFN-α production in the infected lungs between WT and Mint3−/− mice (Fig. 2b). Notably, the level of the type-II interferon IFN-γ was significantly lower in the lungs of Mint3−/− mice than in those of WT mice on day 8 but not on day 4 after infection (Fig. 2b) for unknown reasons. Next, we assessed the induction of humoral acquired immunity against IFV in Mint3−/− mice. WT and Mint3−/− mice were infected again with IFV on day 21 after the first infection (representing the second infection) and the production of virus-specific antibodies was analysed on day 7 after the second infection. Mint3 depletion in mice affected neither the production of virus-specific IgG in the serum nor virus-specific IgA in the lung mucosa (Fig. 2c). Collectively, these data suggest that Mint3 is dispensable for the induction of protective immunity against IFV infection in mice.

View Article: PubMed Central - PubMed

ABSTRACT

Influenza virus (IFV) infection is a common cause of severe pneumonia. Studies have suggested that excessive activation of the host immune system including macrophages is responsible for the severe pathologies mediated by IFV infection. Here, we focused on the X11 protein family member Mint3/Apba3, known to promote ATP production via glycolysis by activating hypoxia inducible factor-1 (HIF-1) in macrophages, and examined its roles in lung pathogenesis and anti-viral defence upon IFV infection. Mint3-deficient mice exhibited improved influenza pneumonia with reduced inflammatory cytokines/chemokine levels and neutrophil infiltration in the IFV-infected lungs without alteration in viral burden, type-I interferon production, or acquired immunity. In macrophages, Mint3 depletion attenuated NF-&kappa;B signalling and the resultant cytokine/chemokine production in response to IFV infection by increasing I&kappa;B&alpha; and activating the cellular energy sensor AMPK, respectively. Thus, Mint3 might represent one of the likely therapeutic targets for the treatment of severe influenza pneumonia without affecting host anti-viral defence through suppressing macrophage cytokine/chemokine production.

No MeSH data available.


Related in: MedlinePlus