Infection with coronavirus proceeds via the respiratory tract, and a large part of the course of the disease takes place there. However, other organs and blood vessels are also affected so that neurological symptoms may occur acutely and later. Thus, the taste is often disturbed, and epileptic seizures, strokes, loss of consciousness and confusion occur. How coronavirus triggers these cognitive and psychiatric symptoms is largely unclear. For example, it is not clear whether coronavirus directly affects brain cells. What is known, however, is that it attacks blood vessels - including those in the brain.
An international consortium led by the Lübeck pharmacologist Prof. Markus Schwaninger (DZHK) wanted to know which mechanism is responsible for brain damage. Therefore, the group focused on the micro blood vessels and the endothelial cells lining them.
The virus triggers cell death program
They found that the coronavirus enters endothelial cells via the ACE2 receptor and triggers a characteristic pathology seen under the microscope. In this process, a viral enzyme destroys the endogenous protein NEMO and initiates a cell death program. A central finding of the study is that endothelial cells and the blood-brain barrier are destroyed in this way.
Possible therapeutic approaches identified
The researchers found a way to block the cell death mechanism. Other proteins are involved in this process. If these are blocked in animal experiments, the endothelial cells do not die. The entire cell death program is deactivated - regardless of whether NEMO was cleaved by the viral enzyme or not. Substances that block cell death protein are already in the early stages of clinical testing. "The results of our study suggest that such drugs could alleviate neurological long covid symptoms in particular," says Markus Schwaninger.
Successful cooperation between several German Centers for Health Research (DZG).
For the study, researchers from the German Centers for Lung Research (DZL), Infection Research (DZIF) and Cardiovascular Research (DZHK) collaborated across disciplines. They used various animal models and samples from Covid-19 patients. An impressive number of different methodologies were used. Of particular note were microscopic methods for visualizing the brain's small blood vessels. "Without our extremely high-resolution STED microscope*, imaging of brain vessels could not have been performed in this way," explains Prof. Peter König (University of Lübeck) of the DZL. He procured the device together with Prof. Gereon Hüttmann (also ARCN) and study leader Schwaninger (DZHK) through the German Research Foundation (DFG).
Original Study: The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Wenzel J, Lampe J, Müller-Fielitz H, Schuster R, Zille M, Müller K, Krohn M, Körbelin J, Zhang L, Özorhan Ü, Neve V, Wagner JUG, Bojkova D, Shumliakivska M, Jiang Y, Fähnrich A, Ott F, Sencio V, Robil C, Pfefferle S, Sauve F, Coêlho CFF, Franz J, Spiecker F, Lembrich B, Binder S, Feller N, König P, Busch H, Collin L, Villaseñor R, Jöhren O, Altmeppen HC, Pasparakis M, Dimmeler S, Cinatl J, Püschel K, Zelic M, Ofengeim D, Stadelmann C, Trottein F, Nogueiras R, Hilgenfeld R, Glatzel M, Prevot V, Schwaninger M, 2021, Nat Neurosci 24: 1522-1533
Source: Press Release DZL-ARNC
