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However, the role of MARCO in antiviral defense is largely unexplored. Here, we investigated whether MARCO might be involved in the innate sensing of infection with adenovirus and recombinant adenoviral vectors by macrophages, which elicit vigorous immune responses<jats:italic>in vivo<\/jats:italic>. Using cells derived from mice, we show that adenovirus infection is significantly more efficient in MARCO-positive alveolar macrophages (AMs) and in AM-like primary macrophage lines (Max Planck Institute cells) than in MARCO-negative bone marrow-derived macrophages. Using antibodies blocking ligand binding to MARCO, as well as gene-deficient and MARCO-transfected cells, we show that MARCO mediates the rapid adenovirus transduction of macrophages. By enhancing adenovirus infection, MARCO contributes to efficient innate virus recognition through the cytoplasmic DNA sensor cGAS. This leads to strong proinflammatory responses, including the production of interleukin-6 (IL-6), alpha\/beta interferon, and mature IL-1\u03b1. These findings contribute to the understanding of viral pathogenesis in macrophages and may open new possibilities for the development of tools to influence the outcome of infection with adenovirus or adenovirus vectors.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Macrophages play crucial roles in inflammation and defense against infection. Several macrophage subtypes have been identified with differing abilities to respond to infection with both natural adenoviruses and recombinant adenoviral vectors. Adenoviruses are important respiratory pathogens that elicit vigorous innate responses<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. The cell surface receptors mediating macrophage type-specific adenovirus sensing are largely unknown. The scavenger receptor MARCO is expressed on some subsets of naive tissue-resident macrophages, including lung alveolar macrophages. Its role in antiviral macrophage responses is largely unexplored. Here, we studied whether the differential expression of MARCO might contribute to the various susceptibilities of macrophage subtypes to adenovirus. We demonstrate that MARCO significantly enhances adenovirus infection and innate responses in macrophages. These results help to understand adenoviral pathogenesis and may open new possibilities to influence the outcome of infection with adenoviruses or adenovirus vectors.<\/jats:p>","DOI":"10.1128\/mbio.00670-17","type":"journal-article","created":{"date-parts":[[2017,8,2]],"date-time":"2017-08-02T00:10:32Z","timestamp":1501632632000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":43,"title":["Key Role of the Scavenger Receptor MARCO in Mediating Adenovirus Infection and Subsequent Innate Responses of Macrophages"],"prefix":"10.1128","volume":"8","author":[{"given":"Mareike D.","family":"Maler","sequence":"first","affiliation":[{"name":"Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany"},{"name":"Allergy Research Group, Department of Dermatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"Faculty of Biology, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Stichling","sequence":"additional","affiliation":[{"name":"Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idan","family":"Cohen","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Ruzsics","sequence":"additional","affiliation":[{"name":"Institute of Virology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor","family":"Wood","sequence":"additional","affiliation":[{"name":"School of Biomedical and Healthcare Sciences, Peninsula Schools of Medicine and Dentistry, University of Plymouth, Plymouth, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy","family":"Engelhard","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarit","family":"Suomalainen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ildiko","family":"Gyory","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Huber","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Medical Center, Justus Liebig University Giessen, Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"M\u00fcller-Quernheim","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang W. A.","family":"Schamel","sequence":"additional","affiliation":[{"name":"BIOSS Centre for Biological Signalling Studies, Faculty of Biology and Center for Chronic Immunodeficiency CCI, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siamon","family":"Gordon","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thilo","family":"Jakob","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Medical Center Giessen and Marburg, Justus Liebig University Giessen, Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan F.","family":"Martin","sequence":"additional","affiliation":[{"name":"Allergy Research Group, Department of Dermatology, Medical Center-University of Freiburg, 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