Discovery of rapid COVID-19 replication mechanism and expanded treatment options
Discovery of the cause of rapid proliferation of COVID-19 (utilization of excessive cellular energy induced by growth signal alteration), confirmation of the potential for COVID-19 treatment through experiments using EGFR inhibitors (e.g., vandetanib)
image: A schematic diagram showing the significant contribution of SCoV2-induced altered mitochondrial dynamics and mitochondrial EGFR translocation in sustaining viral propagation. First, SCOV2 RNA and nucleocapsid complex increases membrane potential during the early stages of SCoV2 infection. This alteration subsequently promotes mitochondrial elongation. SCoV2 also activates the mitochondrial OXPHOS process, thereby promoting ATP production. Second, SCoV2 activates EGFR-mediated cell survival signaling and subsequently promotes mitochondrial EGFR internalization, which contributes to the maintenance of abnormal mitochondrial bioenergetics. These alterations are physiologically relevant to the maintenance of homoeostasis of SCoV2-infected cells and robust SCoV2 propagation.
Credit: Korea Research Institute of Chemical Technology(KRICT)
Concerns about COVID-19 have significantly diminished, but researchers continue to analyze its high transmission rate, aiming to prepare for future infectious diseases. A domestic research team has newly identified the mechanism behind the rapid proliferation of the COVID-19 virus.
Dr. Seong-Jun Kim’s team from the Korea Research Institute of Chemical Technology (KRICT) recently reported in a research paper that the rapid proliferation of COVID-19 is due to altered roles of mitochondria (responsible for energy production in human cells) and EGFR (responsible for growth signal transmission in cells).
Pandemic-causing coronaviruses, such as SARS in 2003, MERS in 2015, and COVID-19 in 2019, have been repeatedly emerging. Given the increasing frequency of such outbreaks, there is an urgent need to accelerate the response to new infectious diseases.
While numerous studies on COVID-19 have been conducted, focusing initially on the viral entry mechanism and vaccine development, recent research has explored methods to hinder viral replication by altering calcium ion concentrations in cells. However, the precise mechanism underlying the rapid replication of the virus after it enters human cells has remained unclear. Understanding this process is crucial for future pandemic preparedness.
Dr. Kim’s team revealed that once COVID-19 invades human cells, it quickly modifies the structure and function of mitochondria to abnormally enhance energy production, which is essential for viral replication. They also discovered that the virus manipulates the EGFR protein, which is critical for cellular growth signaling, to maintain this rapid replication. This increases the likelihood of the virus replicating and spreading in large numbers. Importantly, the team demonstrated through experiments that using EGFR-targeting drugs could effectively treat COVID-19.
Mitochondria: Small organelles within cells that serve as the cell’s powerhouse, generating ATP through oxidative phosphorylation (OXPHOS) and cellular respiration.
EGFR (Epidermal Growth Factor Receptor): A protein that transmits growth and differentiation signals from outside to inside the cell. It is critical for cellular signaling, particularly in epithelial cells covering internal and external surfaces of the body.
The researchers focused on two major phenomena occurring after the virus enters host cells:
(i) Enhanced ATP production: The viral RNA-nucleocapsid complex influences the mitochondrial membrane potential, leading to abnormal increases in energy production. Mitochondria fusion is promoted, increasing surface area and ATP production efficiency.
(ii) Alteration of EGFR function: COVID-19 infection activates the EGFR signaling pathway, with altered EGFR relocating to mitochondria. This sustains excessive energy production, facilitating rapid viral replication.
Using FDA-approved EGFR inhibitors, such as vandetanib and dacomitinib, the team confirmed significant antiviral effects. Notably, vandetanib was highly effective, reducing viral RNA levels in infected mice by 90% after oral administration for three days and significantly alleviating lung inflammation after six days.
Additionally, the antiviral efficacy of vandetanib against COVID-19 variants such as Alpha, Beta, Delta, and Omicron was remarkable, with as much as a 100,000-fold reduction of viral RNA levels in some cases. Vandetanib also effectively prevented the infection of newly produced viral progeny.
The results demonstrate a novel mechanism underlying COVID-19’s rapid replication and suggest the potential for drug repurposing to treat viral infections using existing approved therapies. This discovery could be a significant step toward combating future infectious diseases.
Dr. Kim from the KRICT said, “At a time when we need to prepare for the frequent spread of infectious diseases, the identification of a new mechanism for rapid viral replication and the development of new treatment strategies will contribute to the health and safety of people.”
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KRICT is a non-profit research institute funded by the Korean government. Since its foundation in 1976, KRICT has played a leading role in advancing national chemical technologies in the fields of chemistry, material science, environmental science, and chemical engineering. Now, KRICT is moving forward to become a globally leading research institute tackling the most challenging issues in the field of Chemistry and Engineering and will continue to fulfill its role in developing chemical technologies that benefit the entire world and contribute to maintaining a healthy planet. More detailed information on KRICT can be found at https://www.krict.re.kr/eng/
This paper was published in the prestigious international journal Signal Transduction & Targeted Therapy, which is part of the Nature Portfolio, in May 2024. Dr. Seong-Jun Kim of KRICT is the corresponding author, and Dr. Hye Jin Shin (currently an Assistant Professor at Chungnam National University) is the first author.
The research was supported by KRICT’s basic research projects, the Ministry of Science and ICT’s Bio & Medical Technology Development Program, and various other grants from the Korean government.