People with This Gene Have Higher COVID-19 Mortality Rate [Reading Science]

Professor Sangjun Lee of Ulsan National Institute of Science and Technology Discovers Gene Inducing Excessive Cytokine Secretion

[Asia Economy Reporter Kim Bong-su] A decisive gene that causes death in patients infected with COVID-19 has been discovered.

Ulsan National Institute of Science and Technology (UNIST) announced on the 21st that Professor Lee Sang-jun of the Department of Life Sciences, in collaboration with a U.S. research team, published research findings revealing that ‘ZBP1,’ one of the innate immune sensors that recognize viral infections inside cells, increases the mortality rate of COVID-19 patients.

This gene detects viruses that have invaded cells and signals to produce immune proteins called cytokines. However, in the case of infection by the COVID-19 virus (SARS-CoV-2), it causes the production of an excessive amount of cytokines. This leads to widespread inflammation caused by an overactive immune response throughout the body, resulting in death.

Professor Lee said, “Immune cells play a crucial role in fighting pathogens, but if misregulated, they can attack themselves like a ‘double-edged sword,’ so maintaining a balance in immune cell activation is important,” adding, “This study identified which innate immune sensor disrupts this balance and causes cytokine storms and death.”

The research team used genome-wide CRISPR-Cas9 screening, a gene-editing technology that removes genes from macrophages infected with the COVID-19 virus, to identify the ZBP1 gene. Macrophages containing this gene die due to cytokine storms caused by COVID-19 infection, but macrophages with this gene removed did not die even when infected with the virus.

＜Mechanism of Systemic Inflammation Induced by COVID-19 Virus (SARS-CoV-2)＞
Upon infection with the COVID-19 virus, the innate immune sensor ZBP1, expressed in immune cells such as macrophages, specifically recognizes this virus and triggers simultaneous inflammatory cell death called PANoptosis, leading to systemic inflammation. Image provided by UNIST

According to the study, the ZBP1 gene is particularly adept at recognizing the COVID-19 virus that has invaded cells. While detecting danger signals well is beneficial, the problem lies in producing more cytokines than necessary. Excessive cytokines cause simultaneous inflammatory cell death (PANoptosis). This cell death triggers systemic inflammation, known as a cytokine storm, which increases patient mortality.

The research team also discovered why the commonly used antiviral treatment, interferon (IFN) therapy, is not effective in COVID-19 patients. Interferon strongly induces the expression of the ZBP1 gene, which leads to inflammatory cell death and cytokine storms.

Professor Lee explained, “Interferon is an immune substance secreted after immune sensors recognize viruses and other pathogens. It does not fight the virus directly but acts as a messenger to produce proteins capable of fighting it,” adding, “It is presumed that the ZBP1 gene is more strongly expressed by interferon, causing cytokine storms.”

The relationship between interferon and the ZBP1 gene was also confirmed in small animal experiments infected with the COVID-19 virus. Only when interferon was administered in the presence of the ZBP1 gene did all the animals die. If only one of the two conditions was present, the animals did not all die.

Professor Lee said, “If the expression of the ZBP1 gene can be controlled, it will be possible to develop new drugs that balance immune cell activation and treat COVID-19 patients,” and added, “This approach regulates the immune system in our body to prevent immune inflammatory responses, so it could have broad applicability to treat infections by any virus.”

This research was conducted jointly with the St. Jude Children’s Research Hospital in the United States. The results were published in ‘Science Immunology.’