Olfactory transmucosal SARS-CoV-2 invasion as port of Central Nervous System entry in COVID-19 patients

Meinhardt, Jenny; Radke, Josefine; Dittmayer, Carsten; Mothes, Ronja; Franz, Jonas; Laue, Michael; Schneider, Julia; Brünink, Sebastian; Hassan, Olga; Stenzel, Werner; Windgassen, Marc; Rößler, Larissa; Goebel, Hans-Hilmar; Martin, Hubert; Nitsche, Andreas; Schulz-Schaeffer, Walter J.; Hakroush, Samy; Winkler, Martin S.; Tampe, Björn; Elezkurtaj, Sefer; Horst, David; Oesterhelweg, Lars; Tsokos, Michael; Heppner, Barbara Ingold; Stadelmann, Christine; Drosten, Christian; Corman, Victor Max; Radbruch, Helena; Heppner, Frank L.

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease presenting with fever, cough, and often pneumonia. Moreover, thromboembolic events throughout the body including the central nervous system (CNS) have been described. Given first indication for viral RNA presence in the brain and cerebrospinal fluid and in light of neurological symptoms in a large majority of COVID-19 patients, SARS-CoV-2-penetrance of the CNS is likely. By precisely investigating and anatomically mapping oro- and pharyngeal regions and brains of 32 patients dying from COVID-19, we not only describe CNS infarction due to cerebral thromboembolism, but also demonstrate SARS-CoV-2 neurotropism. SARS-CoV-2 enters the nervous system via trespassing the neuro-mucosal interface in the olfactory mucosa by exploiting the close vicinity of olfactory mucosal and nervous tissue including delicate olfactory and sensitive nerve endings. Subsequently, SARS-CoV-2 follows defined neuroanatomical structures, penetrating defined neuroanatomical areas, including the primary respiratory and cardiovascular control center in the medulla oblongata.