The Impact of the SARS-CoV-2 Virus on the Integrity of the Blood-brain Barrier

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The coronavirus disease (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues to detrimentally impact the prosperity and welfare of our country. As such, fundamental studies are needed to understand the effects of the virus on the organ systems in the body. In these patients, stroke and delirium are not uncommon. These conditions are associated with breakdown of the blood-brain barrier, which is unique to blood vessels in the central nervous system. The work done with this award will study how the spike protein of the virus affects the blood-brain barrier. Specifically, the junctions between cells lining the inside of blood vessels will be studied. The overall goal is to identify the mechanisms underlying the response to the spike protein. The results of this work may suggest new treatment strategies to mitigate the neurological effects of the SARS-CoV-2 virus. This research will be combined with a program to film instructional on-demand science videos for middle and high school science teachers who are teaching remotely during the COVID-19 pandemic.The hypothesis is that binding of the SARS-CoV-2 spike protein to angiotensin converting enzyme 2 (ACE2) disrupts the blood-brain barrier by inhibiting the protective effect of fluid shear stress mediated by RhoA signaling. Recent studies using samples from human patients have demonstrated that vasculature in the brain expresses ACE2, the primary target for the SARS-CoV-2 virus, but the effects of spike protein-mediated inactivation of ACE2 on the integrity of the blood-brain barrier remain unclear. Here, the studies will use a three-dimensional in vitro model of the blood-brain barrier to interrogate the mechanotransduction mechanisms responsible for the endothelial response to the S1 peptide of the spike protein in the presence of fluid shear stress, accounting for both short-term, cytoskeletal-mediated pathways and long-term, transcriptional changes in the endothelial cells. These studies will elucidate the mechanistic basis for breakdown of the blood-brain barrier in response to coronaviruses such as SARS-CoV-2. The results may explain the increased incidence of stroke and other neuropathologies that occur secondary to the COVID-19 virus.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.