Targeting the neurovascular niche in COVID-19

• Applicants: Professor Dr. Manuel A. Friese; Professor Dr. Markus Glatzel
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Pathology
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458698659

• Final Report Year: 2022

Final Report Abstract

In this project we explored neurological complications of COVID-19. Since SARS-CoV-2 has been detected in patients' brain tissues, we first evaluated its entry routes. We were able to show that SARS-CoV-2 brain entry across the blood-brain-barrier results in an increased interferon signaling of the neurovascular unit. This could be reduced by anti-spike-, anti-angiotensinconverting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Having infiltrated the CNS, SARS-CoV-2 invasion seems to be particularly evident in the brain stem. Together with circumastantial evidence that COVID-19 could disturb the vagal system in the brain stem, we next explored whether vagal system damage might be connected to impaired respiratory activity. We were able to provide evidence that vagal nerves are heavily affected in COVID-19. SARS-CoV-2 invades the vagal nerve and initiates immune cell infiltration and subsequent axonal degeneration which results in maladaptive vegetative deterioration in critically ill COVID-19 patients. Finally, post-acute COVID-19 can result in neuropsychiatric sequale. We conducted a cross-sectional study with online questionnaires in health care workers to investigate neurologic manifestations in Long-COVID after infection with Omicron. Notably, we found that persistent neuropsychiatric and somatic symptoms after recovery from SARS-CoV-2 infection in fully vaccinated hospital workers do not occur more frequently than in uninfected individuals.

Publications

• The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Reports, 17(2), 307-320.
  Krasemann, Susanne; Haferkamp, Undine; Pfefferle, Susanne; Woo, Marcel S.; Heinrich, Fabian; Schweizer, Michaela; Appelt-Menzel, Antje; Cubukova, Alevtina; Barenberg, Janica; Leu, Jennifer; Hartmann, Kristin; Thies, Edda; Littau, Jessica Lisa; Sepulveda-Falla, Diego; Zhang, Liang; Ton, Kathy; Liang, Yan; Matschke, Jakob; Ricklefs, Franz; ... & Pless, Ole