Thread by @NeuroVascWenz

Our finding on #SARSCoV2 and the brain´s microvasculature was published in @NatureNeuro today. We used cells, animal models, and #COVID19 patients samples to show that the virus kills brain endothelial cells, possibly explaining neurological symptoms: nature.com/articles/s4159….

A thread: Having clinical data in mind that hints at microvascular changes in COVID-19 patients, we started to look into the microvasculature of brain samples of deceased COVID-19 patients. We found an increased amount of dead capillaries, so-called string vessels.

The control group was well-matched including samples from ventilated and ICU patients. Using different methods we could detect viral entry factors and the virus in brain endothelial cells and we were able to show the same effect in different animal models of SARS-CoV-2 infection.

With having data on other coronaviruses in mind, we wondered whether a SARS-CoV-2 protein could be responsible for endothelial cell death. We focused on the viral main protease Mpro and could show that it cleaves the host cell protein NEMO at 5 cleavage sites.

After expressing the SARS-CoV-2 main protease Mpro specifically in brain endothelial cells in mice using an AAV vector, we found exactly the same microvascular pathology as shown before in COVID-19 patients and SARS-CoV-2 animal models.

In parallel, we developed a mouse model for the loss of NEMO in brain endothelial cells. Again, we found string vessels increased and vascular density decreased. By blocking a specific cell death pathway (necroptosis), we were able to rescue this pathology in those mice.

In a final experiment, we treated mice that express the SARS-CoV-2 main protease in the brain endothelium with a necroptosis inhibitor and found, indeed, the microvascular pathology to be improved.

To summarize, we think, that the direct infection of brain endothelial cells by SARS-CoV-2 leads to the expression of its main protease which cleaves NEMO, an essential protein necessary for the survival of brain endothelial cells.

Our finding might explain at least partially neurological symptoms that not only appear during the acute but also long-term phase of #COVID19 including the increased risk for getting stroke or epileptic seizures and #LongCovid.

Thanks to all collaborators, including @H_M_Fielitz, @MariettaZille, @BuschLab, @umitozorhan, @NeuroendoLille, @GlatzelMarkus, @OJoehren, and the support by @CBBM20, @UniLuebeck, @dfg_public, @EU_Commission, and others to realize this study.

Of course, I have to mention @josephine_lampe who performed a major part of the work and just joined Twitter recently.