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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\u2013treated mice was reduced significantly compared with that in Ad AdrA mut\u2013injected 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-\u03b1R (IFNAR)\u2212\/\u2212 animals were additionally treated with anti\u2013TNF-\u03b1 (Enbrel). Interestingly, albeit less pronounced than in wt mice, in IFNAR\u2212\/\u2212 and Enbrel-treated wt mice, a reduction of serum viremia was achieved\u2014an observation that was lost in anti\u2013TNF-\u03b1\u2013treated IFNAR\u2212\/\u2212 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-\u03b1 are both required and act synergistically.<\/jats:p>","DOI":"10.4049\/jimmunol.2000953","type":"journal-article","created":{"date-parts":[[2020,12,9]],"date-time":"2020-12-09T17:20:39Z","timestamp":1607534439000},"page":"376-385","source":"Crossref","is-referenced-by-count":11,"title":["AdrA as a Potential Immunomodulatory Candidate for STING-Mediated Antiviral Therapy That Required Both Type I IFN and TNF-\u03b1 Production"],"prefix":"10.1093","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0578-6212","authenticated-orcid":false,"given":"Estefania","family":"Rodriguez-Garcia","sequence":"first","affiliation":[{"name":"Terapia G\u00e9nica y Regulaci\u00f3n de la Expresi\u00f3n G\u00e9nica, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, Universidad de Navarra , 31008 Pamplona ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra , 31008 Pamplona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerea","family":"Zabaleta","sequence":"additional","affiliation":[{"name":"Terapia G\u00e9nica y Regulaci\u00f3n de la Expresi\u00f3n G\u00e9nica, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, Universidad de Navarra , 31008 Pamplona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Gil-Farina","sequence":"additional","affiliation":[{"name":"Terapia G\u00e9nica y Regulaci\u00f3n de la Expresi\u00f3n G\u00e9nica, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, Universidad de Navarra , 31008 Pamplona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4873-2588","authenticated-orcid":false,"given":"Manuela","family":"Gonzalez-Aparicio","sequence":"additional","affiliation":[{"name":"Terapia G\u00e9nica y Regulaci\u00f3n de la Expresi\u00f3n G\u00e9nica, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, Universidad de Navarra , 31008 Pamplona ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra , 31008 Pamplona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4153-4549","authenticated-orcid":false,"given":"Maite","family":"Echeverz","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra , 31008 Pamplona ,","place":["Spain"]},{"name":"Laboratorio Patog\u00e9nesis Microbiana, Complejo Hospitalario de Navarra-Universidad P\u00fablica de Navarra, Instituto de Investigaci\u00f3n Sanitaria de Navarra , 31008 Pamplona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"B\u00e4hre","sequence":"additional","affiliation":[{"name":"Research Core Unit Metabolomics, Hannover Medical School , 30625 Hannover 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,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1600-4562","authenticated-orcid":false,"given":"Gloria","family":"Gonzalez-Aseguinolaza","sequence":"additional","affiliation":[{"name":"Terapia G\u00e9nica y Regulaci\u00f3n de la Expresi\u00f3n G\u00e9nica, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, Universidad de Navarra , 31008 Pamplona ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra , 31008 Pamplona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4788-6932","authenticated-orcid":false,"given":"Mirja","family":"Hommel","sequence":"additional","affiliation":[{"name":"Terapia G\u00e9nica y Regulaci\u00f3n de la Expresi\u00f3n G\u00e9nica, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, Universidad de Navarra , 31008 Pamplona ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra 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