SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation.

Area of Science:

• Virology
• Cell Biology
• Mitochondrial Biology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes significant multi-organ damage, but its cellular effects remain unclear.
• Understanding SARS-CoV-2's impact on cellular processes is crucial for developing effective treatments.

Purpose of the Study:

• To investigate SARS-CoV-2-induced cellular alterations, specifically focusing on mitochondrial function and EGFR signaling.
• To identify potential host-targeted therapies for COVID-19.

Main Methods:

• Analysis of mitochondrial bioenergetics and EGFR signaling in SARS-CoV-2 infected cells.
• Assessment of viral propagation and cellular changes upon treatment with EGFR inhibitors.
• Evaluation of vandetanib efficacy in SARS-CoV-2 infected hACE2 transgenic mice.

Main Results:

• SARS-CoV-2 infection abnormally increases mitochondrial transmembrane potential, promotes mitochondrial elongation, and enhances oxidative phosphorylation (OXPHOS) and ATP production.
• The virus activates the EGFR signaling cascade, leading to mitochondrial EGFR trafficking, which supports viral propagation.
• Vandetanib treatment reduced SARS-CoV-2 propagation by inhibiting EGFR trafficking to mitochondria and restoring normal OXPHOS and ATP levels.
• Vandetanib mitigated lung inflammation and reduced viral load in infected mice and showed broad efficacy against SARS-CoV-2 variants.

Conclusions:

• SARS-CoV-2 disrupts mitochondrial dynamics and EGFR trafficking early in infection, crucial for viral spread.
• EGFR represents a promising host target for antiviral therapies against COVID-19.
• Vandetanib demonstrates significant potential as an antiviral agent against SARS-CoV-2 and its variants.