Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism is not fully understood, several studies have shown that neuroinflammation occurs in the acute and post-acute phase. As these studies have predominantly been performed with isolates from 2020, it is unknown if there are differences among SARS-CoV-2 variants in their ability to cause neuroinflammation. Here, we compared the neuroinvasiveness, neurotropism and neurovirulence of the SARS-CoV-2 ancestral strain D614G, the Delta (B.1.617.2) and Omicron BA.1 (B.1.1.529) variants using in vitro and in vivo models. The Omicron BA.1 variant showed reduced neurotropism and neurovirulence compared to Delta and D614G in human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured with astrocytes. Similar differences were obtained in Syrian hamsters inoculated with D614G, Delta and the Omicron BA.1 variant 5 days post infection. Replication in the olfactory mucosa was observed in all hamsters, but most prominently in D614G inoculated hamsters. Furthermore, neuroinvasion into the CNS via the olfactory nerve was observed in D614G, but not Delta or Omicron BA.1 inoculated hamsters. Furthermore, neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G. Altogether, our findings suggest differences in the neuroinvasive, neurotropic and neurovirulent potential between SARS-CoV-2 variants using in vitro hiPSC-derived neural cultures and in vivo in hamsters during the acute phase of the infection.
We thank Imke Visser, Eleanor Marshall, Danny Noack, Debby van Eck-Schipper, J.Maartje Fentener van Vlissingen, Ingeborg van Middelkoop, Rianne Stam, Vincent Duiverman, Lars Vermaat and Vincent Vaes for assistance with the animal studies. This work was funded in part by a fellowship from the Netherlands Organization for Scientific Research (VIDI contract 91718308), a EUR fellowship to D.V.R., NIH contract SAVE to BR and MPGK, Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001) to F.M.S.D.V., H.S. and S.A.K. and an Erasmus MC Human Disease Model Award to F.M.S.D.V. and H.S.
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