Regulation Of Innate Antiviral Immunity By Epinephrine And Norepinephrine

Innate immunity is the first line of host defense against invading of pathogenic microorganisms.Upon viral infection,the intracellular viral nucleic acids act as the mainly pathogen-associated molecular patterns(PAMPs)which are recognized by host pattern recognition receptors(PRRs),leading to the initiation of innate antiviral response.During RNA virus infection,cytosolic viral RNA is sensed by RIG-I/MDA5,and then they are recruited to the mitochondrial-associated adaptor protein VISA(virus-induced signaling adaptor)to transmit signals,which followed by activation of IKKα/β/γ and TBK1/IKKε kinases,and further phosphorylation and activation of transcription factor NF-κB and IRF3 repectively.During DNA virus infection,cytosolic viral DNA is sensed by c GAS,which triggers a conformational change of c GAS and synthesis of the second messenger c GAMP by c GAS.c GAMP binds to and activates the ER membrane-associated adapter protein MITA(mediator of IRF3 activation).The activated MITA recruits TBK1 kinase to mediate the phosphorylation of IRF3,leading to the dimerization and translocation into the nucleus of IRF3,which induces the induction of type I IFNs and hundreds of downsteam effector proteins.Ultimately,these effectors inhibit viral replication,clear virus-infected cells and activate adaptive immune responses.Growing evidence shows that there is a mutual regulation between cell metabolism and immune response.However,regulation of innate antiviral response by humoral metabolism(including hormones and neurotransmitters)has been poorly studied.In addition,it has been demonstrated that stress and anxiety increase the vulnerability to viral infection in human beings,but the underlying mechanism remains enigmatic.In physiological condition,acute stress activates the hypothalamus-pituitary-adrenal cortex axis(HPA)and sympathetic nervous system(SNS),leading to the secretion of stress hormones epinephrine and norepinephrine.These hormones then activate several downstream kinases by binding to the adrenergic receptors on the cell membrane to regulate various biological processes.In this study,we find that levels of epinephrine and norepinephrine,as well as m RNA and protein levels of their β-adrenergic receptors ADRB1 and ADRB2,are down-regulated following viral infection.By studying with mouse and human immune cells,as well as gene-knockout mice,we demonstrate that stress hormones epinephrine and norepinephrine,and their clinical substitute isoprenaline,inhibit innate antiviral response in the ADRB1/2-dependent manner.Upon viral infection,isoprenaline treatment markedly down-regulates the expression of interferons and downstream antiviral genes in the spleens and lungs,promotes viral replication in the spleens and brains,as well as facilitates virus-induced death of mice.The further results show that epinephrine and norepinephrine inhibit virus-induced innate antiviral response via ADRB1/2-mediated activation of PKA.Knockout of PKACA/B reverses isoprenaline-mediated inhibtion of virus-induced innate immune response.Mechanistically,phosphorylation of VISA at T54 by PKACA/B antagonizes the innate immune response to RNA virus,while PKACA/B catalyzes phosphorylation of MITA at S241,S243 and T263 to impair its c GAMP-binding ability and activation,thus inhibiting innate immune response to DNA virus.Collectively,our findings reveal a negative regulatory role of epinephrine and norepinephrine in innate immune response to virus and provide a possible explanation for higher vulnerability to viral infection in stressful or anxious situations.This study improves our understanding of innate immune response regulated by neuroendocrine and provides novel therapeutics for infectious diseases.