AdrA作为STING介导的抗病毒治疗的潜在免疫调节候选物，需要

StephenW

AdrA as a Potential Immunomodulatory Candidate for STING-Mediated Antiviral Therapy That Required Both Type I IFN and TNF-α Production
Estefania Rodriguez-Garcia  1   2 , Nerea Zabaleta  1 , Irene Gil-Farina  1 , Manuela Gonzalez-Aparicio  1   2 , Maite Echeverz  2   3 , Heike Bähre  4 , Cristina Solano  2   3 , Iñigo Lasa  2   3 , Gloria Gonzalez-Aseguinolaza  5   2 , Mirja Hommel  5   2
Affiliations
Affiliations

    1
    Terapia Génica y Regulación de la Expresión Génica, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain.
    2
    Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain.
    3
    Laboratorio Patogénesis Microbiana, Complejo Hospitalario de Navarra-Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain; and.
    4
    Research Core Unit Metabolomics, Hannover Medical School, 30625 Hannover, Germany.
    5
    Terapia Génica y Regulación de la Expresión Génica, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain; [email protected] [email protected].

    PMID: 33298616 DOI: 10.4049/jimmunol.2000953

Abstract

Several dinucleotide cyclases, including cyclic GMP-AMP synthase, and their involvement in STING-mediated immunity have been extensively studied. In this study, we tested five bacterial diguanylate cyclases from the Gram-negative bacterium Salmonella Enteritidis, identifying AdrA as the most potent inducer of a STING-mediated IFN response. AdrA wild-type (wt) or its inactive version AdrA mutant (mut) were delivered by an adenovirus (Ad) vector. Dendritic cells obtained from wt mice and infected in vitro with Ad vector containing AdrA wt, but not mut, had increased activation markers and produced large amounts of several immunostimulatory cytokines. For dendritic cells derived from STING-deficient mice, no activation was detected. The potential antiviral activity of AdrA was addressed in hepatitis B virus (HBV)-transgenic and adenovirus-associated virus (AAV)-HBV mouse models. Viremia in serum of Ad AdrA wt-treated mice was reduced significantly compared with that in Ad AdrA mut-injected mice. The viral load in the liver at sacrifice was in line with this finding. To further elucidate the molecular mechanism(s) by which AdrA confers its antiviral function, the response in mice deficient in STING or its downstream effector molecules was analyzed. wt and IFN-αR (IFNAR)-/- animals were additionally treated with anti-TNF-α (Enbrel). Interestingly, albeit less pronounced than in wt mice, in IFNAR-/- and Enbrel-treated wt mice, a reduction of serum viremia was achieved-an observation that was lost in anti-TNF-α-treated IFNAR-/- animals. No effect of AdrA wt was seen in STING-deficient animals. Thus, although STING is indispensable for the antiviral activity of AdrA, type I IFN and TNF-α are both required and act synergistically.

Copyright © 2020 by The American Association of Immunologists, Inc.

StephenW

AdrA作为STING介导的抗病毒治疗的潜在免疫调节候选物，需要同时产生I型IFN和TNF-α
Estefania Rodriguez-Garcia 1 2，Nerea Zabaleta 1，Irene Gil-Farina 1，Manuela Gonzalez-Aparicio 1 2，Maite Echeverz 2 3，HeikeBähre4，Cristina Solano 2 3，IñigoLasa 2 3，Gloria Gonzalez-Aseguinolaza 5 2， Mirja Hommel 5 2
隶属关系
隶属关系

    1个
    TerapiaGénica和Regulaciónde laExpresiónGénica，研究中心，梅迪卡Aplicada，纳瓦拉大学，西班牙潘普洛纳31008。
    2
    西班牙纳瓦拉卫生研究所（Instituto deInvestigaciónSanitaria de Navarra），西班牙潘普洛纳（31008）。
    3
    纳帕拉纳沃拉大学Complejo HospitalarioPatogénesisMicrobiana实验室，纳帕拉圣保罗研究学院，西班牙潘普洛纳31008；和。
    4
    汉诺威医学院代谢组学研究核心单元，德国汉诺威30625。
    5
    西班牙纳瓦拉大学Apicada中心，西班牙研究中心的TerapiaGénica和Regulaciónde laExpresiónGénica，西班牙潘普洛纳31008； [email protected] [email protected]。

    PMID：33298616 DOI：10.4049 / jimmunol.2000953

抽象

已经广泛研究了包括环GMP-AMP合酶在内的几种二核苷酸环化酶及其与STING介导的免疫的关系。在这项研究中，我们测试了革兰氏阴性细菌肠炎沙门氏菌的5种细菌二鸟苷酸环化酶，确定AdrA是STING介导的IFN反应的最强诱导剂。 AdrA野生型（wt）或非活性形式的AdrA突变体（mut）由腺病毒（Ad）载体递送。从野生型小鼠获得的树突状细胞并在体外用含有AdrA wt（但未突变）的Ad载体体外感染，其激活标志物增加并产生大量的几种免疫刺激性细胞因子。对于源自STING缺陷型小鼠的树突状细胞，未检测到激活。在乙型肝炎病毒（HBV）转基因和腺病毒相关病毒（AAV）-HBV小鼠模型中解决了AdrA的潜在抗病毒活性。与Ad AdrA mut注射的小鼠相比，Ad AdrA wt治疗的小鼠血清中的病毒血症显着降低。处死时肝脏中的病毒载量与该发现一致。为了进一步阐明AdrA赋予其抗病毒功能的分子机制，分析了STING缺陷型小鼠或其下游效应分子的反应。另外，用抗TNF-α（Enbrel）治疗野生型和IFN-αR（IFNAR）-/-动物。有趣的是，尽管不如wt小鼠显着，但在IFNAR-/-和Enbrel处理的wt小鼠中，血清病毒血症降低了，这是在抗TNF-α处理的IFNAR-/-动物中丢失的观察结果。在STING缺陷的动物中未观察到AdrA wt的作用。因此，尽管STING对于AdrA的抗病毒活性是必不可少的，但是I型IFN和TNF-α都是必需的并且协同作用。

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