On March 11, 2020, the World Health Organization (WHO) declared the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as coronavirus disease 2019 (COVID-19).
Despite the discovery of effective COVID-19 vaccines and the subsequent initiation of vaccination programs globally, SARS-CoV-2 infection has been widely reported due to the emergence of new variants that can escape immune responses triggered by both vaccination and natural infection. Thus, novel, rapidly spreading and effective antiviral therapies and treatments are still urgently needed.
Stady: SARS-CoV-2 virus infects human brain organelles causing cell death and loss of synapses that could be salvaged by treatment with sofosbuvir. Image credit: Gorodenkoff/Shutterstock.com
In addition to respiratory distress, COVID-19 patients also experience direct or indirect negative effects on the central nervous system (CNS). Many neurological symptoms, such as stroke, epilepsy, anorexia, aging, hallucinations, and encephalopathy, have been associated with SARS-CoV-2 infection.
One mouse model revealed that the S1 spike protein can cross the blood-brain barrier, suggesting that the virus can infect the brain and induce neurological symptoms. Autopsy reports of patients who died of COVID-19 showed SARS-CoV-2 in cortical neurons. In addition, the possibility of vertical transmission of SARS-CoV-2 to the fetus has been found, which may affect fetal brain development.
Human brain organoids are 3D models of the brain that simulate the cellular and molecular aspects of human embryonic and fetal developmental stages. Previous studies revealed that the functional cortical organelles of the human brain can closely recapitulate the early stages of neural development and the organization of cortical networks.
at recent days PLoS Biology In the study, the researchers discuss how SARS-CoV-2 infects cortical neurons and damages the synapses that form the connection between brain cells. This research not only assesses the risk of SARS-CoV-2 infection in human brain cells, but also analyzes its effect on human brain development.
The TISSUES database has helped identify proteins associated with SARS-CoV-2 infection in the human brain. Some of the proteins expressed in the brain include the transmembrane serine protease 2 (TMPRSS2), angiotensin-converting enzyme 2 (ACE2), neuropilin-1 (NRP1), and CD147, but not CD26.
Entry factor proteins are expressed at a lower level in the central nervous system than in other organs. For example, ACE2 and TMPRSS2 are less expressed compared to NRP1, which is highly expressed in the cerebral cortex and hippocampus. However, the BSG/CD147 gene is highly expressed in all brain regions.
To test whether SARS-CoV-2 can infect the developing human brain, researchers created eight-week-old cerebral cortical organoids (BCO) using skin fibroblasts from healthy donors. Organoids were infected with SARS-CoV-2 to determine whether BCOs were susceptible to SARS-CoV-2 infection.
An important aspect of this research was the identification of FDA-approved antivirals that could relieve neurological symptoms caused by SARS infection. In this study, a BCO infected with influenza A virus, using the same experimental design, was used as a control.
Sofosbuvir (SOF) is an antiviral drug approved by the US Food and Drug Administration (FDA) to treat hepatitis C (HCV). Notably, this drug can also inhibit other single-chain viruses, incl Corona viruses. As a result, the current study was evaluated effectiveness SOF in alleviating neurological manifestations in patients with COVID-19.
Mechanistically, SOF inhibits HCV replication by restricting the activity of RNA dependent RNA polymerase (RdRp). A high degree of sequence and structural similarity was found between the RdRp of SARS-CoV-2 and HCV.
Importantly, SOF-associated residues are conserved among many coronaviruses, including SARS-CoV-2. Given these observations, the authors hypothesized that SOF could effectively prevent the replication of SARS-CoV-2.
A variety of SOF doses have been used in the treatment of BOC. To this end, an overdose of SOF has been found to effectively reduce SARS-CoV-2 intracellular RNA levels.
However, the highest inhibition of SARS-CoV-2 replication, without causing cell death, occurred at a concentration of 20 μM SOF. Furthermore, the efficacy of SOF was validated by analyzing intracellular viral RNA and the number of viable viruses present in the supernatants of SARS-CoV-2-infected BCOs treated with SOF.
Importantly, a reduced number of infectious viruses was detected after antiviral therapy. Immunoblotting and immunoblotting experiments validated the above findings.
Therefore, the experimental results confirmed the effectiveness of SOF in combating COVID-19. Notably, SOF treatment not only reduced SARS-CoV-2 viral protein levels but also reduced virus-induced cell death.
Nestin+ NPCs and MAP2+ neurons were found to be susceptible to SARS-CoV-2 infection. An elevated level of SARS-CoV-2 nucleocapsid proteins in BCO has been associated with increased cell death in both neurons and neural progenitor cells (NPC).
To evaluate the effect of COVID-19 on synapse integrity, the number of excitatory synapses in neurons was measured using Synapsin 1, vGLUT1, and PSD95 antibodies. A significant decrease in presynaptic proteins was observed during SARS-CoV-2 infection, which was effectively attenuated with SOF treatment.
Although experimental results demonstrated SOF’s efficacy in improving neurological conditions in COVID-19 patients, further clinical evaluations are needed for further validation. However, SOF appears to be a promising drug for preventing the development of neurological symptoms in patients with COVID-19.