Reduced replication but increased interferon resistance of SARS-CoV-2 Omicron BA.1
Rayhane Nchioua, Annika Schundner, Susanne Klute, Lennart Koepke, Maximilian Hirschenberger, Sabrina Noettger, Giorgio Fois, Fabian Zech, Alexander Graf, Stefan Krebs, Peter Braubach, Helmut Blum, Steffen Stenger, Dorota Kmieć, Manfred Frick, Frank Kirchhoff, Konstantin M. J. Sparrer
Abstract
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.