Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease (COVID-19), is currently infecting millions of people worldwide and is causing drastic changes in people’s lives. Recent studies have shown that neurological symptoms are a major issue for people infected with SARS-CoV-2. However, the mechanism through which the pathological effects emerge is still unclear. Brain endothelial cells (ECs), one of the components of the blood–brain barrier, are a major hurdle for the entry of pathogenic or infectious agents into the brain. They strongly express angiotensin converting enzyme 2 (ACE2) for its normal physiological function, which is also well-known to be an opportunistic receptor for SARS-CoV-2 spike protein, facilitating their entry into host cells. First, we identified rapid internalization of the receptor-binding domain (RBD) S1 domain (S1) and active trimer (Trimer) of SARS-CoV-2 spike protein through ACE2 in brain ECs. Moreover, internalized S1 increased Rab5, an early endosomal marker while Trimer decreased Rab5 in the brain ECs. Similarly, the permeability of transferrin and dextran was increased in S1 treatment but decreased in Trimer, respectively. Furthermore, S1 and Trimer both induced mitochondrial damage including functional deficits in mitochondrial respiration. Overall, this study shows that SARS-CoV-2 itself has toxic effects on the brain ECs including defective molecular delivery and metabolic function, suggesting a potential pathological mechanism to induce neurological signs in the brain.
Highlights
Coronavirus disease 2019 (COVID-19) is infecting millions of people worldwide and has caused drastic changes in the lives of people [1]
This is an interesting phenomenon because the spike protein does not contain a nuclear localization signal, and it can potentially exert its role in gene regulation for effective cell invasion
Our results indicate that the spike protein from SARSCoV-2 can induce mitochondrial damage to the brain endothelial cells (ECs) affecting their respiratory function, possibly leading to the neurological symptoms observed in patients with COVID-19
Summary
Coronavirus disease 2019 (COVID-19) is infecting millions of people worldwide and has caused drastic changes in the lives of people [1]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent that causes COVID-19, is an enveloped RNA virus that belongs to the beta coronavirus [5]. SARS-CoV-2 is composed of four different structural proteins, including spike, envelope, membrane, and nucleocapsid protein [6]. Among these structural proteins, the spike protein has received the most attention, as it can induce potent immune responses and is a ligand for angiotensin converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 [7,8]. The high infectivity of SARS-CoV-2 stems from the ability to bind to ACE2 much stronger than that of severe acute respiratory syndrome coronavirus (SARS-CoV) [9]. The spike protein bound to ACE2 is further cleaved into S1/S2 by cellular proteases, including cell surface, lysosomal, and extracellular proteases [7]
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