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AdrA as a Potential Immunomodulatory Candidate for STING-Mediated Antiviral Therapy That Required Both Type I IFN and TNF-α Production

Estefania Rodriguez-Garcia, Nerea Zabaleta, Irene Gil-Farina, Manuela Gonzalez-Aparicio, Maite Echeverz, Heike Bähre, Cristina Solano, Iñigo Lasa, Gloria Gonzalez-Aseguinolaza and Mirja Hommel
J Immunol January 15, 2021, 206 (2) 376-385; DOI: https://doi.org/10.4049/jimmunol.2000953
Estefania Rodriguez-Garcia
*Terapia Génica y Regulación de la Expresión Génica, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain;
†Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
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Nerea Zabaleta
*Terapia Génica y Regulación de la Expresión Génica, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain;
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Irene Gil-Farina
*Terapia Génica y Regulación de la Expresión Génica, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain;
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Manuela Gonzalez-Aparicio
*Terapia Génica y Regulación de la Expresión Génica, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain;
†Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
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Maite Echeverz
†Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
‡Laboratorio Patogénesis Microbiana, Complejo Hospitalario de Navarra-Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain; and
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Heike Bähre
§Research Core Unit Metabolomics, Hannover Medical School, 30625 Hannover, Germany
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Cristina Solano
†Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
‡Laboratorio Patogénesis Microbiana, Complejo Hospitalario de Navarra-Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain; and
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Iñigo Lasa
†Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
‡Laboratorio Patogénesis Microbiana, Complejo Hospitalario de Navarra-Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain; and
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Gloria Gonzalez-Aseguinolaza
*Terapia Génica y Regulación de la Expresión Génica, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain;
†Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
‡Laboratorio Patogénesis Microbiana, Complejo Hospitalario de Navarra-Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain; and
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Mirja Hommel
*Terapia Génica y Regulación de la Expresión Génica, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain;
†Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
‡Laboratorio Patogénesis Microbiana, Complejo Hospitalario de Navarra-Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain; and
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Key Points

  • Antiviral activity of the c-di-GMP cyclase AdrA is STING dependent.

  • An optimal AdrA-induced response requires synergistic action of type I IFN and TNF-α.

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.

Footnotes

  • This work was supported by Secretaria de Estado de Investigación, Desarrollo e Innovación, Ministerio de Economia y Competitividad, Ministerio de Ciencia y Tecnología Grants SAF2015-70028-R and RTI2018-101936-B-I00 (to G.G.-A.). E.R.-G. was supported by a Basque Country Fellowship. I.G.-F. was supported by Formación de Personal en Investigación Fellowship of the Spanish Ministry of Economy and Competitiveness, and N.Z. was supported by La Fundación para la Investigación Médica Aplicada Fellowship.

  • Abbreviations used in this article:

    Ad
    adenovirus
    Ad AdrA mut
    Ad vector containing AdrA mut
    Ad AdrA wt
    Ad vector containing AdrA wt
    BMDC
    bone marrow–derived DC
    c-di-GMP
    cyclic-di-GMP
    CDN
    cyclic dinucleotide
    c-GAMP
    cyclic GMP–AMP
    cGAS
    c-GAMP synthase
    DC
    dendritic cell
    HBcAg
    hepatitis B core Ag
    HBV
    hepatitis B virus
    HBVtg
    HBV-transgenic
    hSTING
    human STING
    IFNAR−/−
    deficient for the IFN-αR
    IHC
    immunohistochemistry
    ISG
    IFN-stimulated gene
    S. Enteritidis
    Salmonella enterica serovar Enteritidis
    STING
    stimulator of IFN genes
    sTNFR1
    soluble TNF receptor I
    TMEM173
    transmembrane protein 173
    vg
    viral genome
    wt
    wild-type.

  • Received August 14, 2020.
  • Accepted November 9, 2020.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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AdrA as a Potential Immunomodulatory Candidate for STING-Mediated Antiviral Therapy That Required Both Type I IFN and TNF-α Production
Estefania Rodriguez-Garcia, Nerea Zabaleta, Irene Gil-Farina, Manuela Gonzalez-Aparicio, Maite Echeverz, Heike Bähre, Cristina Solano, Iñigo Lasa, Gloria Gonzalez-Aseguinolaza, Mirja Hommel
The Journal of Immunology January 15, 2021, 206 (2) 376-385; DOI: 10.4049/jimmunol.2000953

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AdrA as a Potential Immunomodulatory Candidate for STING-Mediated Antiviral Therapy That Required Both Type I IFN and TNF-α Production
Estefania Rodriguez-Garcia, Nerea Zabaleta, Irene Gil-Farina, Manuela Gonzalez-Aparicio, Maite Echeverz, Heike Bähre, Cristina Solano, Iñigo Lasa, Gloria Gonzalez-Aseguinolaza, Mirja Hommel
The Journal of Immunology January 15, 2021, 206 (2) 376-385; DOI: 10.4049/jimmunol.2000953
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Print ISSN 0022-1767        Online ISSN 1550-6606