Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants
Guilherme Dias de Melo, Victoire Perraud, Flavio Alvarez, Alba Vieites‐Prado, Seonhee Kim, Lauriane Kergoat, Anthony Coléon, Bettina Salome Trüeb, Magali Tichit, Aurèle Piazza, Agnès Thierry, David Hardy, Nicolas Wolff, Sandie Munier, Romain Koszul, Etienne Simon‐Lorière, Volker Thiel, Marc Lecuit, Pierre‐Marie Lledo, Nicolas Renier, Florence Larrous, Hervé Bourhy
Abstract
Anosmia 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 develop 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 are 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 validate the olfactory pathway as a major entry point into the brain in vivo and demonstrate in vitro that SARS-CoV-2 travels retrogradely and anterogradely along axons in microfluidic neuron-epithelial networks.