SARS-CoV-2 Omicron has rapidly become the dominant variant worldwide. Omicron has 30 mutations in the spike protein compared to the ancestral Wuhan-Hu-1 strain, and recent studies have detailed how these mutations contribute to viral escape from antibody responses in convalescent or vaccinated individuals. However, whether mutations in Omicron spike protein affect virus entry into host cells and host tropism has yet to be explored.

Three recent preprints (not peer-reviewed) have sought to functionally characterize Omicron in comparison to previous variants of concern. Key findings from Meng et al., using a pseudotyped virus, are that Omicron replicates less efficiently in lung organoids and lung epithelial cells compared with the Delta variant and with Wuhan-Hu-1. Peacock et al. and Willett et al. also reported significantly lower viral copy numbers following Omicron infection of lung epithelial cells compared with Delta or Wuhan-Hu-1. However, Peacock et al. also noted an increase in viral copy number in Omicron-infected human nasal airway epithelial cells. These findings hint at a mechanism that could contribute to increased transmissibility of Omicron, as well as its apparent reduced disease severity.

All three studies conclude that Omicron has a reduced ability to induce syncytia in tissue culture, which potentially has clinical significance because syncytia formation has been associated with increased disease severity. Syncytia formation usually requires viral infection through membrane fusion involving TMPRSS2. The low rate of syncytia formation with Omicron infection suggests that it may have switched to using endosomal fusion through cathepsins instead. Confirming this, Willett et al. found that infection with pseudotyped Omicron virus was reduced in cells expressing high levels of TMPRSS2 but increased in cells that only support endosomal entry. Furthermore, by blocking TMPRSS2-mediated cell-surface fusion and/or cathepsin-mediated endosomal fusion, Willett et al. and Peacock et al. determined that Omicron can use both entry routes but prefers endosomal fusion to cell-surface fusion. The ability to infect cells by both routes considerably increases the number of cell types that Omicron can infect.

Finally, Peacock et al. observed that Omicron can use ACE2 receptors from a larger range of host species than other variants, including mice and domestic poultry. This raises the possibility that SARS-CoV-2 could form a long-term reservoir in a new animal host for future human outbreaks.