2023-06-22 11:45:41
When we breathe, the SARS-CoV-2 virus enters the body through the cells of the upper respiratory tract. The first line of defense are the epithelial cells: If they perceive an intruder, they sound the alarm and the innate immune system attacks in a targeted manner. Only if they can understand these reactions and manipulate them pharmacologically can researchers develop effective treatments against viral diseases such as COVID-19 or other emerging infections. For such analyzes, researchers at the Max Delbrück Center have modified lung epithelial cells in the laboratory in such a way that they light up red as soon as a cell triggers an immune response.
Originally, Dr. Gaetano Gargiulo, head of the “Molecular Oncology” working group, and his team developed this approach for cancer research. But during the pandemic, they also tested their method on virus-infected cells. “Our team wanted to play its part in managing the pandemic with a tool to research and fight viral infections,” says Gargiulo, the senior author of the study. “We may be able to deal with future pandemics more quickly if we adapt the technology to new strains of the virus.”
The immune response in real time
The tool, called the ‘synthetic locus control region’ (sLCR), consists of a lab-created stretch of DNA that turns a fluorescent protein on or off depending on whether the cell is priming an immune response. During an innate immune response, sLCR turns on and forms a protein that glows red under a fluorescence microscope. In this way you can see whether the cell has registered the infection and how hard it is fighting against it.
The researchers used unique DNA sequences for their sLCR: Based on previous studies, they assumed that they are active during a SARS-CoV-2 infection. They then inserted the sequences into epithelial cells in the petri dish and infected the cells with the SARS-CoV-2 virus. As soon as the biochemical signals of the innate immune response triggered an infection, a clear signal appeared under a fluorescence microscope: the cells lit up red.
“What I found most exciting was that infection with different strains of the live virus actually triggered the color coding,” says Ben Jiang, a PhD student in Gargiulo’s group and one of the first authors of the study. The experiments with live virus particles were made possible thanks to the collaboration between the team at the Max Delbrück Center and Luka Cicin-Sain’s group at the Helmholtz Center for Infection Research (HZI) in Braunschweig.
Finding new treatments for viral diseases
Thanks to this simple evaluation, the researchers were able to search for drugs that inhibit or enhance the immune response. Some drugs for rheumatoid arthritis, for example, did not make the treated cells glow red – an indication that they are blocking the immune response. Certain chemotherapy treatments, on the other hand, caused the cells to glow more intensely. This suggests that they enhance the immune response.
The different effects could be useful in different phases of a COVID-19 infection. A drug that elicits a strong immune response would help fight the virus early in the infection. In the later course, however, a persistent immune reaction could worsen the clinical picture. “With this technology, we can identify active substances that strengthen or weaken the immune response of the epithelial tissue. Both can make sense – depending on the stage of the disease and symptoms,” explains Jiang.
In particular, the discovery that DNA-damaging substances can amplify the alarm signal from epithelial cells makes low-dose radiotherapy a potential treatment for viral infections, including COVID-19. This has been tested during the pandemic, but requires precise dosing and good timing, Gargiulo says.
Although the present study was conducted on cell cultures, other research groups have already examined the identified drugs in clinical trials for COVID-19 therapy. The results of Gargiulo and his team could therefore help to find new combinations and other active ingredients that still have to be tested for their effectiveness in humans. “This technology could also be tried out with more complex disease models such as organoids or mice,” says Matthias Schmitt, another first author of the study.
“The same approach can easily be repurposed for other viral infections, such as the emerging threat of dengue and Zika viruses,” says Gargiulo. “And it is available to laboratories worldwide to find timely drugs against new infectious diseases.” (Science Advances; doi: 10.1126/sciadv.adf4975)
Source: Max Delbrück Center for Molecular Medicine in the Helmholtz Association
22. June 2023
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