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The host range of IAVs is shaped by species\u2010specific virus\u2010host interactions, and several host barriers have been identified that restrict the adaptation of avian viruses to humans. We used a comparative interaction screen by mammalian cell\u2010based Nanoluciferase two\u2010hybrid (mN2H) assay to investigate whether differences in the interaction networks between viral proteins from human, avian, and zoonotic IAVs and a curated panel of human innate immune factors could serve as indicators of the zoonotic potential of avian IAVs. The results revealed both conserved and strain\u2010specific interactions, while underscoring limitations in comparing interactions across independent screens. Complementary functional analyses by siRNA knockdowns identified cellular factors and pathways potentially involved in host restriction, as well as pro\u2010viral factors that could represent potential antiviral targets. The comparative interactomic mN2H approach holds promise for evaluating avian IAV zoonotic potential, but our findings highlighted the need for further studies using broader cellular libraries to fully validate its predictive value.<\/jats:p>","DOI":"10.1002\/pmic.70155","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T13:23:28Z","timestamp":1781875408000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Toward Predicting Pandemic Potential: A Comparative Analysis of Virus\u2010Host Interactions Between Diverse Influenza A Viruses and the Human Innate Immune System"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9000-9058","authenticated-orcid":false,"given":"Antoine","family":"Gerodez","sequence":"first","affiliation":[{"name":"Sciensano, National Influenza Centre Brussels Belgium"},{"name":"Sciensano, Avian Virology and Immunology Brussels 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