It has been more than two years since the outbreak of the new crown pneumonia epidemic, which has spread globally and caused up to 580 million infections and more than 6 million deaths; the new coronavirus (SARS-CoV-2) enters the human body mainly through the spike protein on the surface of the virus. protein, S protein) binds to the ACE2 receptor on the surface of human respiratory epithelial cells to infect cells. However, normal epithelial cells actually only express a low amount of ACE2 protein, but it quickly induces acute and severe respiratory symptoms after infection. The mechanism of rapid transmission has the opportunity to find methods and strategies to reduce the infection.
Tan Zehua, Distinguished Researcher of the Center for Immunomedicine Research of the National Health Institute, and Assistant Researcher Zhuang Huaijia’s team found that the expression of protein kinase MAP4K3 (also known as GLK) in cells infected with the new coronavirus was higher than that in normal cells, and the proportion of epithelial cells with high GLK expression was significantly higher than that in normal cells. The severity of the disease is positively correlated, and in cooperation with Zhou Yanhong, a researcher at the Institute of Infectious Diseases and Vaccines of the National Institutes of Health, the use of live new coronavirus mouse experiments confirmed that this infection mechanism is the key to the substantial infection of the new coronavirus, and can also explain the side effects caused by the new coronavirus vaccine. mechanism. The research results will be published in the world-renowned medical journal “EMBO Molecular Medicine” in July 2022.
The research team analyzed the single-cell RNA sequencing results of COVID-19 patient samples and unexpectedly found that after the new coronavirus entered the host epithelial cells, the spike protein would induce high expression of the protein kinase GLK. Continued use of proteomics and various biochemical experiments confirmed that overexpressed GLK phosphorylates ACE2 protein, allowing ACE2 to escape the ubiquitination degradation mechanism of ubiquitinase UBR4, resulting in a stable increase of ACE2 protein on the cell surface. At the same time, the overexpression of GLK induces the release of exosomes loaded with ACE2 protein, which are transmitted to other cells with low ACE2 expression. These cells that have received ACE2 protein are more likely to be infected by the new coronavirus.
The researchers analyzed the serum samples of COVID-19 patients and found that GLK phosphorylated ACE2 protein and exosomes loaded with ACE2 protein increased significantly compared with normal samples. These research results confirm that the excess expression of protein kinase GLK is a key factor in the pathogenesis of COVID-19, and also explain the reason why the new coronavirus quickly induces clinical symptoms and is easy to spread.
The research team used the mouse model to conduct animal experiments. When the small molecule inhibitor of GLK (verteporfin) was used to reduce the amount of ACE2 protein on the cell surface and reduce the production of ACE2 exosomes, the infection rate of the new coronary pneumonia virus in mice was successfully suppressed. . Verteporfin and other drugs that can modulate GLK and ACE2 have the potential to be candidate drugs for inhibiting new coronavirus infection.
In addition, the research results can further explain the mechanism of severe inflammatory response caused by new coronary pneumonia and the side effects of new coronary pneumonia vaccine. The main component of the new coronary pneumonia vaccine is spike protein or spike protein RNA. Spike protein may also stimulate and induce immune cells to produce excessive GLK, resulting in a strong inflammatory response and side effects of the vaccine. It is expected that by further unraveling the pathogenic mechanism of the disease, it will help the research and development and screening of therapeutic drugs and vaccines, develop novel medical methods for relieving disease symptoms, and promote the well-being of all people.
Full research paper: https://www.embopress.org/doi/10.15252/emmm.202215904