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Understanding how immune cells contribute to RSV pathogenesis is crucial for developing interventions. However, the lack of model systems that accurately mimic\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      immune responses has hampered progress in this field. Here, we present iPSC-derived macrophages (iMacs) as a promising model for the analysis of tissue-resident macrophage responses during RSV infection. Using monocyte-derived macrophages as a comparison, we show that iMacs are less susceptible to RSV infection. RNA-Seq of iMacs and monocyte-derived macrophages revealed fundamental differences in the baseline expression of immune-related genes between the cell types. Differences in permissiveness were attributed to interferon (IFN) signaling, as a deficiency in IFNAR signaling increased iMac susceptibility to RSV infection, accompanied by increased syncytia formation. These findings present iMacs as a promising research model system for primary macrophages and identify the IFN signaling cascade as a crucial aspect of antiviral responses during RSV infection.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Respiratory syncytial virus (RSV) infections remain a global health burden, with persistent gaps in understanding immune responses that may contribute to disease severity. Early innate immune responses by tissue-resident macrophages are a crucial factor in restricting RSV spread, yet limitations in accessible models have hindered progress in understanding their contribution to protective and harmful immune responses. This study presents iPSC-derived macrophages (iMacs) as a reliable and accessible tool that more accurately replicates the tissue-resident macrophage state compared to monocyte-derived alternatives. Our findings demonstrate the crucial role of effective interferon signaling in limiting susceptibility to RSV infection and the formation of RSV-induced syncytia. Disruptions in interferon signaling increased susceptibility, viral replication, and syncytia formation, revealing key host factors involved in RSV-induced cytopathology. The presented iMac model, therefore, provides deeper insights into protective immune responses, guiding improved therapies and model systems for respiratory virus research.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00845-26","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:11:12Z","timestamp":1783948272000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["iPSC-based macrophage models reveal interferon-dependent control of RSV permissiveness and syncytia formation"],"prefix":"10.1128","volume":"14","author":[{"given":"Ayse","family":"Agac","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vayv672","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Queiros","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00f2yqf98","id-type":"ROR","asserted-by":"publisher"}],"name":"Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School (MHH)","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini","family":"Nikolouli","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00f2yqf98","id-type":"ROR","asserted-by":"publisher"}],"name":"Department for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School (MHH)","place":["Hannover, Germany"]},{"id":[{"id":"https:\/\/ror.org\/00f2yqf98","id-type":"ROR","asserted-by":"publisher"}],"name":"Cluster of Excellence\u2013Resolving Infection Susceptibility, RESIST Hannover Medical School, EXC 2155","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christin","family":"Knittler","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vayv672","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariane H. 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