TY - JOUR T1 - Reduced replication but increased interferon resistance of SARS-CoV-2 Omicron BA.1 JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201745 VL - 6 IS - 6 SP - e202201745 AU - Rayhane Nchioua AU - Annika Schundner AU - Susanne Klute AU - Lennart Koepke AU - Maximilian Hirschenberger AU - Sabrina Noettger AU - Giorgio Fois AU - Fabian Zech AU - Alexander Graf AU - Stefan Krebs AU - Peter Braubach AU - Helmut Blum AU - Steffen Stenger AU - Dorota Kmiec AU - Manfred Frick AU - Frank Kirchhoff AU - Konstantin MJ Sparrer Y1 - 2023/06/01 UR - https://www.life-science-alliance.org/content/6/6/e202201745.abstract N2 - The IFN system constitutes a powerful antiviral defense machinery. Consequently, effective IFN responses protect against severe COVID-19 and exogenous IFNs inhibit SARS-CoV-2 in vitro. However, emerging SARS-CoV-2 variants of concern (VOCs) may have evolved reduced IFN sensitivity. Here, we determined differences in replication and IFN susceptibility of an early SARS-CoV-2 isolate (NL-02-2020) and the Alpha, Beta, Gamma, Delta, and Omicron VOCs in Calu-3 cells, iPSC-derived alveolar type-II cells (iAT2) and air–liquid interface (ALI) cultures of primary human airway epithelial cells. Our data show that Alpha, Beta, and Gamma replicated to similar levels as NL-02-2020. In comparison, Delta consistently yielded higher viral RNA levels, whereas Omicron was attenuated. All viruses were inhibited by type-I, -II, and -III IFNs, albeit to varying extend. Overall, Alpha was slightly less sensitive to IFNs than NL-02-2020, whereas Beta, Gamma, and Delta remained fully sensitive. Strikingly, Omicron BA.1 was least restricted by exogenous IFNs in all cell models. Our results suggest that enhanced innate immune evasion rather than higher replication capacity contributed to the effective spread of Omicron BA.1. ER -