Nikhil Prasad Fact checked by:Thailand Medical News Team Jul 22, 2024 5 months, 18 hours, 40 minutes ago
COVID-19 News: A New Approach to Combatting COVID-19
In an exciting development, researchers from The Children's Hospital of Philadelphia-USA and the University of Pennsylvania-USA have uncovered a promising strategy to combat COVID-19. This
COVID-19 News report dives into the details of their groundbreaking study, which focuses on the role of mitochondrial antioxidants in reducing the severity of SARS-CoV-2 infection in mice.
Proposed mitochondrial bioenergetic pathophysiology of SARS-CoV-2 infection and its mitigation by the mCAT transgene and EUK8 treatment. SARS-CoV-2 inhibits mitochondrial OXPHOS at both the protein and transcriptional levels 1) and floods the cell and mitochondria with Ca++ via the viroporins E and Orf3a 2) resulting in increased mitochondrial ROS production. Left Arm: The increased mROS stabilizes and activates HIF-1α which up-regulates glycolysis and down-regulates OXPHOS redirecting substrates from oxidative energy production to provide substates for viral propagation. Middle and Right Arm: Increased mROS and mitochondrial Ca++ activated the mtPTP to release fragmented and oxidized mtDNA into the cytosol. Middle Arm: cytosolic mtDNA interacts with TLR9, cGAS of the cGAS-STING pathway, and ZBP1 which interacts with MAVS molecule to activate the NFκB and interferon inflammation pathways. Right Arm: Oxidized mtDNA fragments interact with the NLRP3 inflammasome to activate CASP1 which processed pro-IL-1β to IL-1β which is secreted and activates the inflammation pathways. CASP1 also processes the GSDMD precursor to activated GSDMD which initiates pyroptosis and cell death.
The COVID-19 Challenge
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, continues to mutate, making it increasingly challenging to manage and control. Current vaccines and treatments primarily target the viral spike (S) protein, which frequently undergoes changes, leading to potential resistance. Researchers, therefore, sought a more durable solution that wouldn't be easily thwarted by the virus's ability to mutate.
Understanding the Virus's Strategy
SARS-CoV-2 has a cunning mechanism to enhance its replication within host cells. The virus inhibits mitochondrial oxidative phosphorylation (OXPHOS), a crucial process for cellular energy production. This inhibition leads to an increase in mitochondrial reactive oxygen species (mROS), which, in turn, activates hypoxia-inducible factor-1alpha (HIF-1α). HIF-1α shifts cellular metabolism from OXPHOS to glycolysis, redirecting resources to support viral replication. This metabolic shift not only aids in viral propagation but also triggers the release of mitochondrial DNA (mtDNA), activating the body's innate immune response and contributing to inflammation.
The Role of Mitochondrial Antioxidants
T
o counteract this viral strategy, the research team explored the potential of boosting the mitochondrial antioxidant capacity in mice. They used two approaches: genetically engineering mice to express mitochondrially targeted catalase (mCAT) and administering a pharmacological antioxidant called Eukarion 8 (EUK8). The results were promising.
Key Findings from the Study
The study revealed several significant findings:
-Reduced Weight Loss and Disease Severity: Mice expressing mCAT or treated with EUK8 experienced less weight loss and showed milder symptoms compared to untreated mice.
-Lower Levels of mtDNA and Inflammation: The interventions led to reduced levels of circulating mtDNA and lower lung levels of HIF-1α, viral proteins, and inflammatory cytokines.
-Enhanced OXPHOS Gene Expression: RNA sequencing of infected lungs showed that both mCAT and EUK8 upregulated OXPHOS gene expression and downregulated genes associated with HIF-1α and innate immune response.
Broader Implications: This approach is not subject to viral resistance mutations, making it a potentially effective strategy against other viruses that employ similar mechanisms.
The researchers further conducted a series of experiments to validate their findings:
-Systemic Expression of mCAT: In mice engineered to express both human ACE2 (hACE2) and mCAT, the systemic expression of mCAT reversed the OXPHOS defect caused by SARS-CoV-2. This was evidenced by decreased weight loss and improved clinical scores. Additionally, there was a significant reduction in lung levels of HIF-1α, viral proteins, and inflammatory cytokines.
-EUK8 Treatment: Similar to mCAT, treatment with EUK8 also mitigated the effects of the virus. EUK8-treated mice exhibited less weight loss, reduced clinical severity, and lower levels of viral proteins and inflammatory markers.
-RNA Sequencing Analysis: The RNA sequencing of lung samples from infected mice confirmed that both mCAT and EUK8 treatments led to upregulation of OXPHOS genes and downregulation of glycolytic and inflammatory genes. This indicates a restoration of normal cellular metabolism and a reduction in the virus-induced immune response.
A Promising Future for Antioxidant Therapy
The findings from this study suggest that mitochondrial antioxidants like mCAT and EUK8 could provide a powerful new approach to treating COVID-19. By targeting the host's cellular metabolism rather than the virus itself, this strategy avoids the issue of viral mutations leading to drug resistance.
Broader Implications for Other Viral Infections
The researchers believe that this approach could be generalizable to other viral infections that exploit similar mechanisms. By enhancing the host's mitochondrial antioxidant capacity, it may be possible to mitigate the severity of various viral diseases.
Conclusion
This innovative research provides a new perspective on how to tackle COVID-19 and potentially other viral infections. By focusing on the host's cellular mechanisms, mitochondrial antioxidants offer a promising avenue for developing more effective and durable treatments.
The study findings were published in the peer-reviewed journal: PNAS.
https://www.pnas.org/doi/10.1073/pnas.2321972121
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https://www.thailandmedical.news/news/covid-19-research-study-proposes-redox-hypothesis-to-explain-as-to-why-certain-individuals-are-vulnerable-to-sars-cov-2-antioxidants-can-help-
https://www.thailandmedical.news/news/covid-19-and-our-cells-powerhouses-mitochondria
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