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Biologists identify key factor in immune system response to viral infection

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The COVID-19 pandemic has underscored the urgency for science to continue to unravel how viruses infect and how immune systems respond to such threats.

Researchers at the University of California, San Diego studying how small worms defend themselves against pathogens have discovered a gene that acts as a cell’s first line response against infection. Division of Biological Sciences postdoctoral researcher Vladimir Lažetić, Professor Emily Troemel and their colleagues at UC San Diego and New York University’s Grossman School of Medicine identified the key role of ” ZIP-1,” a protein called a transcription factor, which helps convert genetic information from DNA to messenger RNA.

The discovery, published on January 10 in Nature Communication, could have implications for identifying similar genes that control immune responses to infection in humans.

“By better understanding immunity against viral infection, we can identify new ways to treat viral infection,” said Troemel, a professor in the Section of Cellular and Developmental Biology. “The new antiviral factor we have identified gives us a better idea of ​​immunity and how worms fight viral infections. Worms detect an RNA virus in a similar way to how humans detect an RNA virus like the coronavirus.

During the study, researchers at UC San Diego used fluorescence to track viral infection. The image shows Ascaris intestinal cells infected with the virus d’Orsay (red) and the expression of the ZIP-1 protein (green, indicated by arrows) which is induced only in the presence of the DRH-1 receptor.

The researchers studied Caenorhabditis elegans, a tiny roundworm with a transparent body that allows scientists to closely monitor how an infection invades a living animal. Lažetić used a fluorescent tracking method to identify which parts of roundworm cells are involved in a response to infection. He was surprised that ZIP-1 appeared so early in the defense process. In addition to viruses, ZIP-1 also jump-started defenses against infection by a cell-invading fungus, the data revealed.

“We found that the subset of genes controlled by ZIP-1 is important for immunity, but not for some other phenotypes that we see in other animals that have activated this immune response,” said Lažetić, who noted that the name ZIP-1 comes from its intended zipper-like structure. “We also observed that ZIP-1 is activated by a previously described receptor that is important for triggering antiviral immunity, both in mammals and in humans. C.elegans, so there are links that can be made with human immunity.

For Troemel, the most surprising aspect of the results was that ZIP-1 acts as a centralized hub for the immune response against a number of threats.

“A virus, fungus, and heat stress are all so different, but we found that they all cross the same central ZIP-1 hub to activate a set of immune genes,” Troemel said. “Understanding the early role of ZIP-1 is important because we know timing is so important in terms of immune response. This is one of the lessons we learned with COVID. If you have an early response to interferon, that tends to correlate very well with fighting infection.

Troemel’s lab is now digging deeper into the details of the discovery, including studying how the receptor that worms use to detect a virus, which is similar to a receptor humans use in the immune response, communicates with ZIP-1 in the process. defense.

“Revolutions in biology have often come from understanding how simple organisms cope with threats such as infection,” Troemel said. “Studies that may seem abstract can lead to groundbreaking discoveries.”

the Nature Communication co-authors of the article include Vladimir Lažetić, Fengting Wu (undergraduate student), Lianne Cohen (graduate student), Kirthi Reddy, Ya-Ting Chang, Spencer Gang, Gira Bhabha, and Emily Troemel.

The research was funded by the National Institutes of Health (R01 AG052622 and GM114139), the National Institute of General Medical Sciences/NIH (K12GM068524), and the American Heart Association Postdoctoral Award (19POST34460023).