Earlier this month, multiple health departments confirmed that BA.2.86- a highly mutated SARS-CoV-2 virus that causes COVID-19- poses a risk of rapid transmission in countries around the world. This week, the latest vaccination plan will be launched across the United States, but it remains to be seen whether this latest vaccination plan will effectively slow down the spread of BA.2.86 or other new virus variants.
However, vaccines remain the most powerful treatment tool for preventing and slowing down the spread of COVID-19. However, in a new study, researchers from Yale University in the United States found that a defense protein in the lungs and other non-immune tissue cells may one day provide more treatment options, especially for those susceptible to severe COVID-19 infection. The relevant research results were recently published in the journal Nature, with the title “PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection”.
The human immune system – a complex network of organs, proteins, and cells – works together to provide protective responses to foreign invaders such as viruses and bacteria. When scientists mention the cells that make up the human immune system, they traditionally refer to cells derived from bone marrow, such as B cells, T cells, macrophages, and dendritic cells.
But in reality, the human immune system is not a closed system, but permeates every part of our physiology. Cells that have little or no relationship with the bone marrow, such as epithelial cells in the respiratory or digestive tract, liver cells in the liver, or nerve cells that transmit signals in the brain, as part of the cellular innate immune system, can also play an important role in combating viruses or other pathogens.
Unlike antibodies, these mechanisms typically do not “remember” the specific pathogens they encounter, but they can respond to commands from T cells, which do have immune memory. MacMicking and his collaborators learned that the first contact with SARS-CoV-2 usually occurs in the respiratory tract, so they tried to trigger lung epithelial cells to fight against the virus without relying on the body’s antibody response.
MacMicking said, “The protective immunity against SARS-CoV-2 not only relies on antibodies produced during vaccination or infection, but also on activating host defense proteins within infected cells to help control infection. This situation occurs throughout the body: of course, in the respiratory tract, but also in many target tissues. In fact, cells that are not usually considered part of the immune system often produce the local defense protein that directly inhibits SARS-CoV-2 under the guidance of the immune system.
The vaccine against SARS-CoV-2 or other viruses works by producing neutralizing antibodies that can bind to this virus after human infection. Over time, as the virus spreads and mutates, vaccines may struggle to keep up with the emergence of new strains that evade antibody neutralization. In addition, as far as COVID-19 is concerned, it is currently unclear why some people may experience mild or no symptoms of the disease, while others may become terminally ill.
New ways to prevent replication
Recognizing these challenges, MacMicking and his collaborators conducted research on the human genome to find new ways to interfere with the replication of the SARS-CoV-2 virus in human cells, especially respiratory cells.
These authors found that cells located inside the lungs and other tissues express a protein called phospholipid crawlase 1 (PLSCR1), which can prevent SARS-CoV-2 replication before the virus spreads to nearby cells. This protein is expressed in cells before infection, but when activated by interferon (IFN), it begins to work effectively. This local cellular autoimmunity plays an important role in protecting the mucosal barrier and target tissues against deadly pathogens, including those that cause tuberculosis, typhoid fever, and AIDS.
With this knowledge, MacMicking and his team began studying whether cellular autoimmunity can be used to combat SARS-CoV-2.
MacMicking said, “Scientists are not very familiar with the atypical immune system – a population of cells derived from outside the bone marrow – and their role in resisting infections. Our laboratory is working to improve understanding of these poorly studied cell types, which have not been considered part of the immune system. In fact, just like immune cells participate in the balance of each organ system, the situation may be exactly the opposite – each organ’s cells contribute to immunity, including direct defense against infection.”
In addition to helping to redefine the boundaries of our immune system, MacMicking and his team’s research on PLSCR1 may one day point out new treatment strategies for treating or preventing COVID-19. This type of treatment method may be used in conjunction with vaccines or other antibody-based therapies, especially for novel SARS-CoV-2 strains that have an evasion effect on certain antibody types.
Charles Rice, a professor of virology at Rockefeller University, said, “This is an excellent research achievement that allows us to gain a deeper understanding of the complex defense mechanisms in cells that protect us from infection and disease. A deeper understanding of how PLSCR1 prevents SARS-CoV-2 infection may provide a new perspective for the development of widely effective antiviral drugs.”
The research results of MacMicking and his team also bring hope to patients with severe COVID-19 who are not effective in rehabilitative plasma or remdesivir treatment. In this regard, pilot studies have shown that IFN therapy can provide another treatment pathway. Previous studies by Jean Laurent Casanova’s laboratory at Rockefeller University have shown a close relationship between severe COVID-19 and individuals carrying gene mutations that inhibit interferon signal transduction.
MacMicking said, “If we can find a way to turn on the PLCSR1 gene in individuals with missing interferon signals, or completely bypass the need for such signals, then it may become a useful way to consider new therapeutic interventions for SARS-CoV-2. In addition, by screening patients for PLSCR1 gene mutations, doctors may identify high-risk populations with severe COVID-19 symptoms.”
Although these research results by MacMicking and his collaborators are convincing, this is only the first step in finding new treatments for COVID-19 and other viruses.
One of the biggest obstacles faced by these authors is that IFN can activate hundreds of different host defense proteins, including those that may not be beneficial for the clinical course of COVID-19. MacMicking said, “Knowing which proteins are useful and which proteins are not, we can take measures to develop a small molecule or drug that may mimic the effects of PLSCR1 without expressing IFN-induced proteins that may be detrimental to the host.”
He added that their next task is to map the natural structure of this protein. Once we know exactly how this protein looks at the atomic level, we can better predict how it blocks SARS-CoV-2 and design drugs that promote its activity.
Although this new study mainly focuses on SARS-CoV-2, it may have a broader impact on how to design prevention and treatment methods for other viruses.
MacMicking said, “In terms of human health, we don’t have that many antiviral drugs, which is different from the situation with bacteria. Our antibiotic reserves have always been much larger. Nowadays, our antiviral drugs mainly include vaccines, nucleoside or polymerase inhibitors, but these drugs have certain limitations.”
“Considering this, one of our team’s goals is to expand our antiviral capabilities. If we can start thinking about how to appropriately activate local or tissue-resident immunity, especially the antiviral proteins involved, then we can try designing chemicals or drugs to better activate these pathways.”
Featured Products
Protein Pre-coupled Magnetic Beads
Related Services
Protein Expression and Purification Services
Cytokine and Receptor Analysis
Integrated Drug Development & Manufacturing Bioprocess Development
Reference
Dijin Xu et al. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature, 2023, doi:10.1038/s41586-023-06322-y.