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Key Protein Modification in Immune Response to Viruses Identified by Cleveland Clinic Researchers
Researchers at the Cleveland Clinic have discovered that a specific alteration to the immune protein MDA5 plays a crucial role in how the human body detects and responds to viral infections and replication.
The findings, published in the journal PNAS, detail how two crucial protein modifications activate MDA5, enabling it to identify viral intruders, curb viral replication, and mount an effective immune response. This mechanism is vital for preventing severe complications associated with viral infections, such as heart inflammation caused by viruses.
This latest research builds upon earlier studies from the laboratory of Dr. Michaela Gack, the scientific director at Cleveland Clinic’s Florida Research & Innovation Center. The team’s ongoing mission is to deepen our understanding of viral detection in the body, with hopes of translating these insights into new antiviral therapies applicable to various viruses.
Protein modifications involve the addition of extra molecules or chemical groups to proteins after their initial synthesis. While genes provide the blueprint for creating proteins, the finished product requires further refinement through enzymatic processes that prepare proteins for their specific functions or signal them for degradation. These modifications are integral, allowing for precise regulation of various biological processes.
MDA5 is essential in the initial steps of viral detection within the human body. Certain modification sites within MDA5 facilitate its response to viral presence. A small protein known as ISG15 binds to these sites through a process called ISGylation, as articulated by the study’s first author, Dr. Lucky Sarkar, a postdoctoral researcher in Dr. Gack’s lab.
To investigate the significance of this protein modification in viral sensing, the research team collaborated with the Case Western Reserve Transgenic and Targeting Facility to create a preclinical model of MDA5 that lacked ISG15 attachment sites.
“Removing the ability of the protein to undergo this specific modification had effects almost identical to outright deleting the protein,” noted Dr. Sarkar. “This demonstrates that the ISG15 modification of MDA5 is crucial for the activation of innate immunity, which serves as the body’s primary defense against infections.”
In the absence of MDA5 ISGylation, models infected with the encephalomyocarditis virus (EMCV) exhibited markedly more severe symptoms, including increased viral replication and heightened heart inflammation.
Previous investigations by Dr. Gack’s team have indicated that MDA5 is capable of recognizing various viral families, including coronaviruses and those transmitted by mosquitoes.
“Our work has shown that MDA5 utilizes ISGylation to detect viral invaders upon their entry into the body,” stated Dr. Gack. “This modification is a crucial mechanism facilitating our immune system’s response to a diverse array of viruses. Understanding these basic processes is essential for developing comprehensive antiviral therapies.”
According to Drs. Gack and Sarkar, these insights could pave the way for the creation of broad-spectrum antiviral medications. Current antiviral research typically targets specific viruses through vaccines or tailored treatments. While these methods are effective for single viral targets, they are not universally applicable.
“Our current research aims to determine whether we can manipulate these protein modifications to enhance our innate immune response, thereby creating a broadly effective antiviral strategy for multiple viral infections,” Dr. Gack explained. “Such an advancement would significantly alter the approach to emerging pathogens and situations where traditional treatments have not yielded success.”
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