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

• Published in: Nature communications Vol. 14; no. 1; pp. 4485 - 14
• Main Authors: de Melo, Guilherme Dias, Perraud, Victoire, Alvarez, Flavio, Vieites-Prado, Alba, Kim, Seonhee, Kergoat, Lauriane, Coleon, Anthony, Trüeb, Bettina Salome, Tichit, Magali, Piazza, Aurèle, Thierry, Agnès, Hardy, David, Wolff, Nicolas, Munier, Sandie, Koszul, Romain, Simon-Lorière, Etienne, Thiel, Volker, Lecuit, Marc, Lledo, Pierre-Marie, Renier, Nicolas, Larrous, Florence, Bourhy, Hervé
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.07.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/62; 14; 14/19; 14/5; 38/39; 38/77; 631/326/596/4130; 631/378/2624/1703; 692/420/254; 96/63; Animals; Anosmia; Axons; Axons - virology; Central nervous system; COVID-19; COVID-19 - virology; Cricetinae; Deletion mutant; Genetic Variation; Genome, Viral; Hamsters; Humanities and Social Sciences; Infections; Inflammation; Invasiveness; Life Sciences; Microfluidics; multidisciplinary; Olfaction; Olfaction disorders; Olfactory Bulb - virology; Pandemics; SARS-CoV-2 - genetics; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Viral diseases; Viral Load; Virus Internalization
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40228-7

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. Here, Dias de Melo et al. assess the clinical, olfactory, and neuroinflammatory conditions of golden hamsters infected with SARS-CoV-2 wt and VOCs and report that viruses can infect neurons, travel inside axons, and invade the central nervous system.