Ex vivo models show how Omicron replicates in upper and lower respiratory tissues, it's cell entry mechanism and it's pathogenicity.
Emergence of SARS-CoV-2 variants of concern (VOC) with progressively increased transmissibility between humans is a threat to global public health. The omicron variant also evades immunity from natural infection or vaccines1, but it is unclear whether its exceptional transmissibility is due to immune evasion or intrinsic virological properties. We compared the replication competence and cellular tropism of the wild-type (WT) virus, D614G, Alpha, Beta, Delta and Omicron variants in ex vivo explant cultures of human bronchus and lung. Dependence on TMPRSS2 for infection was also evaluated. We show that Omicron replicated faster than all other SARS-CoV-2 in the bronchus but less efficiently in the lung parenchyma. All VOCs had similar cellular tropism as the WT. Omicron was more dependent on cathepsins than other VOC tested, suggesting that the omicron variant enters cells by a different route than other variants. The lower replication competence of Omicron in human lung may explain the reduced severity of Omicron that is now being reported in epidemiological studies although determinants of severity are multifactorial. These findings provide important biological correlates to observed epidemiological observations.