New signal to trigger human immune response

Researchers from the Cleveland Clinic’s Florida Research and Innovation Center (FRIC) have found that disruption of a cellular structure, known as the actin cytoskeleton, is a “priming signal” for the body to respond to a virus. These findings, published in Cell this week, could lay the groundwork for the development of new vaccines and antiviral treatments.

Previously, viral genetic material such as RNA was thought to be the only requirement for certain sensor molecules that live in cells to trigger an immune response – an “alarm system” for many cell types. RNA also serves as the basis for vaccines by training a patient’s immune system to recognize a virus. This new study showed that the signaling process also requires disrupting the actin cytoskeleton inside cells, which occurs when a virus infects cells.

“This is a fundamental new way of looking at how the immune system can be activated, and the implications are that it could lead to broad antiviral therapeutics,” says Michaela Gack, Ph.D., Arthur and Marylin Chair Levitt Endowed and scientific director of the FRIC. “Our data show that this process is common to different types of RNA viruses. »

Cytoskeletons, made up of the protein actin, serve as structural support for cells, but are also essential in processes such as the cell’s ability to grow, divide and internalize key substances. A virus disrupts the cytoskeleton, but so do vaccine components and some treatments, says Dr. Gack.

“It is unknown whether this process is detected by our cellular immune surveillance system and can trigger an antiviral response,” says Dr. Gack. “Our work has shown that specific immune receptors detect virus-induced actin cytoskeleton rearrangements and then sound the alarm. »

Although it has been around for decades, interest in using RNA as the basis for vaccines and therapeutics has grown exponentially during the COVID-19 pandemic. Research has shown that the trigger system is similar for several viruses, including Zika, influenza, or SARS-CoV-2, the virus that causes COVID-19.

Dr. Gack’s team, including lead author Dhiraj Acharya, Ph.D., a research associate at FRIC, also found that lipid components or virus-like particles such as those used in vaccines or therapies based on RNA can cause the disruption of the cytoskeleton necessary to elicit an immune response. These results could help developers “refine” the immunostimulatory potencies of therapeutics or vaccines.

Dr. Gack’s lab, operating under the Cleveland Clinic’s Multi-site Global Center for Pathogen and Human Health Research, studies virus-host interactions at the molecular level, identifying host responses that may play a key role in the development of new treatments and vaccines. The center is a cornerstone of the Cleveland Innovation District.

The study was a collaboration with Konstantin Sparrer, Ph.D., University of Ulm in Germany, and other collaborators from several institutions. Funding was provided by the National Institutes of Health, the German Federal Ministry of Education and Research and the German Research Foundation.

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Materials provided by Cleveland Clinic. Note: Content may be edited for style and length.

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