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OMV uptake by host cells activates TLR signalling via transported PAMPs. As important resident immune cells, alveolar macrophages are located at the air-tissue interface where they comprise the first line of defence against inhaled microorganisms and particles. To date, little is known about the interplay between alveolar macrophages and OMVs from pathogenic bacteria. The immune response to OMVs and underlying mechanisms are still elusive. Here, we investigated the response of primary human macrophages to bacterial vesicles (\n                    <jats:italic>Legionella<\/jats:italic>\n                    \u00a0\n                    <jats:italic>pneumophila<\/jats:italic>\n                    ,\n                    <jats:italic>Klebsiella<\/jats:italic>\n                    \u00a0\n                    <jats:italic>pneumoniae<\/jats:italic>\n                    ,\n                    <jats:italic>Escherichia\u00a0coli<\/jats:italic>\n                    ,\n                    <jats:italic>Salmonella<\/jats:italic>\n                    \u00a0\n                    <jats:italic>enterica<\/jats:italic>\n                    ,\n                    <jats:italic>Streptococcus<\/jats:italic>\n                    \u00a0\n                    <jats:italic>pneumoniae<\/jats:italic>\n                    ) and observed comparable NF-\u03baB activation across all tested vesicles. In contrast, we describe differential type I IFN signalling with prolonged STAT1 phosphorylation and strong Mx1 induction, blocking influenza A virus replication only for\n                    <jats:italic>Klebsiella<\/jats:italic>\n                    ,\n                    <jats:italic>E.coli<\/jats:italic>\n                    and\n                    <jats:italic>Salmonella<\/jats:italic>\n                    OMVs. OMV-induced antiviral effects were less pronounced for endotoxin-free\n                    <jats:italic>Clear coli<\/jats:italic>\n                    OMVs and Polymyxin-treated OMVs. LPS stimulation could not mimic this antiviral status, while TRIF knockout abrogated it. Importantly, supernatant from OMV-treated macrophages induced an antiviral response in alveolar epithelial cells (AEC), suggesting OMV-induced intercellular communication. Finally, results were validated in an ex vivo infection model with primary human lung tissue. In conclusion,\n                    <jats:italic>Klebsiella<\/jats:italic>\n                    ,\n                    <jats:italic>E.coli<\/jats:italic>\n                    and\n                    <jats:italic>Salmonella<\/jats:italic>\n                    OMVs induce antiviral immunity in macrophages via TLR4-TRIF-signaling to reduce viral replication in macrophages, AECs and lung tissue. These gram-negative bacteria induce antiviral immunity in the lung through OMVs, with a potential decisive and tremendous impact on bacterial and viral coinfection outcome.\n                  <\/jats:p>","DOI":"10.1186\/s12964-023-01086-4","type":"journal-article","created":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T05:03:06Z","timestamp":1679979786000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Bacterial vesicles block viral replication in macrophages via TLR4-TRIF-axis"],"prefix":"10.1186","volume":"21","author":[{"given":"Jeff","family":"Bierwagen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Wiegand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Laakmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Danov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Limburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie Muriel","family":"Herbel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Heimerl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Dorna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Jonigk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Preu\u00dfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilhelm","family":"Bertrams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherina","family":"Sewald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon N.","family":"Schulte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Pogge von Strandmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"B\u00f6ttcher-Friebertsh\u00e4user","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Schmeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Lena","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,28]]},"reference":[{"key":"1086_CR1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1146\/annurev.micro.091208.073413","volume":"64","author":"A Kulp","year":"2010","unstructured":"Kulp A, Kuehn MJ. 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