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In addition to their role in many prokaryotic processes, they can interact with cells of the host immune system, enabling a potential for medical application. This study investigated how bEVs from various pathogenic bacteria modulate human macrophage immune responses and their subsequent ability to protect lung alveolar epithelial cells against SARS-CoV-2 infection.<\/jats:p>\n                  <jats:p>\n                    Primary human blood-derived macrophages were stimulated with bEVs derived from\n                    <jats:italic>Legionella pneumophila<\/jats:italic>\n                    (\n                    <jats:italic>Lp<\/jats:italic>\n                    ),\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    (\n                    <jats:italic>Kp<\/jats:italic>\n                    ),\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    (\n                    <jats:italic>Ec<\/jats:italic>\n                    ),\n                    <jats:italic>Salmonella Typhimurium<\/jats:italic>\n                    (\n                    <jats:italic>Sal<\/jats:italic>\n                    ) and\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    (\n                    <jats:italic>Sp<\/jats:italic>\n                    ). bEVs from\n                    <jats:italic>Kp<\/jats:italic>\n                    ,\n                    <jats:italic>Ec<\/jats:italic>\n                    and\n                    <jats:italic>Sal<\/jats:italic>\n                    strongly induced pro-inflammatory cytokines and interferon-stimulated genes via Toll-like receptor 4-dependent signaling. In contrast, bEVs from\n                    <jats:italic>Lp<\/jats:italic>\n                    or\n                    <jats:italic>Sp<\/jats:italic>\n                    elicited minimal or no immune response. Conditioned media from\n                    <jats:italic>Kp<\/jats:italic>\n                    -,\n                    <jats:italic>Ec<\/jats:italic>\n                    - or\n                    <jats:italic>Sal<\/jats:italic>\n                    - bEV-stimulated macrophages further influenced Calu-3 epithelial cells, leading to the induction of interferon-stimulated genes. Notably, SARS-CoV-2 propagation tended to be reduced in Calu-3 cells pre-stimulated with conditioned media from\n                    <jats:italic>Kp<\/jats:italic>\n                    -bEV- and\n                    <jats:italic>Ec<\/jats:italic>\n                    -bEV-treated macrophages, as demonstrated by decreased infectious virus titers in TCID\n                    <jats:sub>50<\/jats:sub>\n                    assays.\n                  <\/jats:p>\n                  <jats:p>\n                    These findings provide new insights into macrophage-bEV interactions, demonstrating that gram-negative\n                    <jats:italic>Kp<\/jats:italic>\n                    - and\n                    <jats:italic>Ec<\/jats:italic>\n                    -derived bEVs induce a potent interferon-dependent antiviral state that can be propagated to lung epithelial cells in vitro. This study highlights a macrophage-driven mechanism of innate immune modulation that extends beyond immune cells to shape antiviral responsiveness in structural cells, providing a conceptual framework for future immunomodulatory or vaccine-oriented strategies.\n                  <\/jats:p>","DOI":"10.1186\/s12964-026-03003-x","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T07:05:24Z","timestamp":1782284724000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bacterial extracellular vesicles modulate epithelial antiviral responses via macrophage-mediated immunomodulation"],"prefix":"10.1186","volume":"24","author":[{"given":"Jeff","family":"Bierwagen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mosche","family":"L\u00fcckhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam Ruth","family":"Heindl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"B\u00f6ttcher-Friebertsh\u00e4user","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Rummel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Lehmann","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":[[2026,6,24]]},"reference":[{"issue":"3","key":"3003_CR1","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.jinf.2020.01.014","volume":"80","author":"JW Tang","year":"2020","unstructured":"Tang JW, Tambyah PA, Hui DSC. 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