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Despite causing regular seasonal epidemics with substantial morbidity, mortality and socioeconomic burden, there is still a lack of research into influenza B viruses (IBVs). In this study, we provide for the first time a systematic investigation on the tropism, replication kinetics and pathogenesis of IBVs in the human respiratory tract.Physiologically relevant ex vivo explant cultures of human bronchus and lung, human airway organoids, and in vitro cultures of differentiated primary human bronchial epithelial cells and type-I-like alveolar epithelial cells were used to study the cellular and tissue tropism, replication competence and induced innate immune response of 16 IBV strains isolated from 1940 to 2012 in comparison with human seasonal influenza A viruses (IAVs), H1N1 and H3N2. IBVs from the diverged Yamagata- and Victoria-like lineages and the earlier undiverged period were included.The majority of IBVs replicated productively in human bronchus and lung with similar competence to seasonal IAVs. IBVs infected a variety of cell types, including ciliated cells, club cells, goblet cells and basal cells, in human airway organoids. Like seasonal IAVs, IBVs are low inducers of pro-inflammatory cytokines and chemokines. Most results suggested a higher preference for the conducting airway than the lower lung and strain-specific rather than lineage-specific pathogenicity of IBVs.Our results highlighted the non-negligible virulence of IBVs which require more attention and further investigation to alleviate the disease burden, especially when treatment options are limited., Competing Interests: Conflict of interest: C.H.T. Bui has nothing to disclose. Conflict of interest: M.M.T. Ng has nothing to disclose. Conflict of interest: M.C. Cheung has nothing to disclose. Conflict of interest: K-C. Ng has nothing to disclose. Conflict of interest: M.P.K. Chan has nothing to disclose. Conflict of interest: L.L.Y. Chan has nothing to disclose. Conflict of interest: J.H.M. Fong has nothing to disclose. Conflict of interest: J.M. Nicholls has nothing to disclose. Conflict of interest: J.S.M. Peiris reports grants from the Research Grants Council of the Hong Kong SAR and the US National Institute of Allergy and Infectious Diseases (NIAID), during the conduct of the study. Conflict of interest: R.W.Y Chan reports grants from the Research Fund Secretariat, Food and Health Bureau, Hong Kong Special Administrative Region, during the conduct of the study. Conflict of interest: M.C.W. Chan reports grants from the Research Grants Council of the Hong Kong SAR and the US National Institute of Allergy and Infectious Diseases (NIAID), during the conduct of the study., (Copyright ©ERS 2019.)