Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Institute of General Physiology, Ulm University Medical Center, Ulm, Germany.
Life Sci Alliance. 2023 Mar 28;6(6). doi: 10.26508/lsa.202201745. Print 2023 Jun.
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.
IFN 系统构成了强大的抗病毒防御机制。因此，有效的 IFN 反应可预防严重的 COVID-19，外源性 IFN 可抑制 SARS-CoV-2 的体外复制。然而，新兴的 SARS-CoV-2 关注变异株（VOCs）可能已经进化出对 IFN 的敏感性降低。在这里，我们确定了 Calu-3 细胞、iPSC 衍生的肺泡 II 型细胞（iAT2）和原代人气道上皮细胞的气液界面（ALI）培养物中早期 SARS-CoV-2 分离株（NL-02-2020）与 Alpha、Beta、Gamma、Delta 和 Omicron VOC 之间在复制和 IFN 敏感性方面的差异。我们的数据表明，Alpha、Beta 和 Gamma 的复制水平与 NL-02-2020 相似。相比之下，Delta 始终产生更高的病毒 RNA 水平，而 Omicron 则减弱。所有病毒均被 I 型、II 型和 III 型 IFN 抑制，尽管抑制程度不同。总体而言，Alpha 对 IFN 的敏感性略低于 NL-02-2020，而 Beta、Gamma 和 Delta 仍然完全敏感。值得注意的是，在所有细胞模型中，Omicron BA.1 对外源 IFN 的限制最小。我们的结果表明，增强的先天免疫逃避而不是更高的复制能力导致了 Omicron BA.1 的有效传播。
