Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

de Melo, G. D.; Perraud, V.; Alvarez, F.; Vieites-Prado, A.; Kim, S.; Kergoat, L.; Trueb, B. S.; Tichit, M.; Piazza, A.; Thierry, A.; Hardy, D.; Wolff, N.; Munier, S.; Koszul, R.; Simon-Loriere, E.; Thiel, V.; Lecuit, M.; Lledo, P.-M.; Renier, N.; Larrous, F.; Bourhy, H.

doi:10.1101/2022.08.31.505985

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bioRxiv · 10.1101/2022.08.31.505985

Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

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Abstract

SUMMARYAnosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Here, we assessed the clinical, olfactory and neuroinflammatory conditions of golden hamsters infected with the original Wuhan SARS-CoV-2 strain, its isogenic ORF7-deletion mutant and three variants: Gamma, Delta, and Omicron/BA.1. We show that infected animals developed a variant-dependent clinical disease including anosmia, and that the ORF7 of SARS-CoV-2 contributes to the induction of olfactory dysfunction. Conversely, all SARS- CoV-2 variants were found to be neuroinvasive, regardless of the clinical presentation they induce. Taken together, this confirms that neuroinvasion and anosmia are independent phenomena upon SARS-CoV-2 infection. Using newly generated nanoluciferase-expressing SARS-CoV-2, we validated the olfactory pathway as a major entry point into the brain in vivo and demonstrated in vitro that SARS-CoV-2 travels retrogradely and anterogradely along axons in microfluidic neuron-epithelial networks. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=151 HEIGHT=200 SRC="FIGDIR/small/505985v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@8225ceorg.highwire.dtl.DTLVardef@80342aorg.highwire.dtl.DTLVardef@e0dfd1org.highwire.dtl.DTLVardef@1861e13_HPS_FORMAT_FIGEXP M_FIG C_FIG

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de Melo, G. D., Perraud, V., Alvarez, F., Vieites-Prado, A., Kim, S., Kergoat, L., Trueb, B. S., Tichit, M., Piazza, A., Thierry, A., Hardy, D., Wolff, N., Munier, S., Koszul, R., Simon-Loriere, E., Thiel, V., Lecuit, M., Lledo, P.-M., Renier, N., Larrous, F., Bourhy, H.. 2022-08-31. Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants. https://doi.org/10.1101/2022.08.31.505985

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