Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiv...Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiviral response is regulated by neuronal endocrine functions is unclear. Here, we show that viral infection reduced the serum levels of the β-adrenergic hormones epinephrine and norepinephrine as well as the cellular levels of their receptors ADRB1 and ADRB2. We further show that an increase in epinephrine/norepinephrine level inhibited the innate antiviral response in an ADRB1-/2-dependent manner. Mechanistically, epinephrine/norepinephrine stimulation activated the downstream kinase PKA, which catalyzed the phosphorylation of MITA at S241, S243 and T263, inhibiting MITA activation and suppressing the innate immune response to DNA virus. In addition, phosphorylation of VISA at T54 by PKA antagonized the innate immune response to RNA virus. These findings reveal the regulatory mechanisms of innate antiviral responses by epinephrine/norepinephrine and provide a possible explanation for increased host susceptibility to viral infection in stressful and anxiety-promoting situations.展开更多
Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic.We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice.Progesterone induces...Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic.We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice.Progesterone induces downstream antiviral genes and promotes innate antiviral response in cells and mice,whereas knockout of the progesterone receptor PGR has opposite effects.Mechanistically,stimulation of PGR by progesterone activates the tyrosine kinase SRC,which phosphorylates the transcriptional factor IRF3 at Y107.展开更多
基金supported by grants from the National Natural Science Foundation of China(32188101,31830024,31922021 and 32170713)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiviral response is regulated by neuronal endocrine functions is unclear. Here, we show that viral infection reduced the serum levels of the β-adrenergic hormones epinephrine and norepinephrine as well as the cellular levels of their receptors ADRB1 and ADRB2. We further show that an increase in epinephrine/norepinephrine level inhibited the innate antiviral response in an ADRB1-/2-dependent manner. Mechanistically, epinephrine/norepinephrine stimulation activated the downstream kinase PKA, which catalyzed the phosphorylation of MITA at S241, S243 and T263, inhibiting MITA activation and suppressing the innate immune response to DNA virus. In addition, phosphorylation of VISA at T54 by PKA antagonized the innate immune response to RNA virus. These findings reveal the regulatory mechanisms of innate antiviral responses by epinephrine/norepinephrine and provide a possible explanation for increased host susceptibility to viral infection in stressful and anxiety-promoting situations.
基金This work was supported by grants from the State Key R&D Program of China(2017YFA0505800 and 2021YFA1302400)the National Natural Science Foundation of China(31922021,32170713,31830042,and 31771555)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic.We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice.Progesterone induces downstream antiviral genes and promotes innate antiviral response in cells and mice,whereas knockout of the progesterone receptor PGR has opposite effects.Mechanistically,stimulation of PGR by progesterone activates the tyrosine kinase SRC,which phosphorylates the transcriptional factor IRF3 at Y107.
