Researchers are becoming more interested in enhancing our natural defenses to fight a variety of health problems more effectively. In new work that investigated how our immune system controls microbial infections, scientists have discovered how a molecule called USP18 can help regulate immune signaling. They found that USP18 keeps the immune response under control but paradoxically, can also make us vulnerable to additional infection. The findings have been reported in Science Immunology.
"I call the molecule a wolf in sheep's clothing," said the co-first author of the study Namir Shaabani, Ph.D., a postdoctoral researcher at Scripps Research.
At the initial stage of a viral infection, the immune system utilizes a type of molecule called a type 1 interferon to combat the virus. After the invading virus is under control, levels of type 1 interferon go down. In this study, scientists aimed to learn more about why interferon-stimulated genes (ISGs) that encourage the immune system to fight viruses also dampen the infected host’s ability to fight off infections in the first place, explained the senior author of the work John Teijaro, Ph.D., assistant professor at Scripps Research.
One such ISG is USP18. When researchers deleted the USP18 gene from a type of immune cell in a mouse model, they found that the ability to fight off infection from two different kinds of Gram-positive bacteria was enhanced.
When USP18 was activated under normal circumstances, the antimicrobial responses of mice were impaired. The team found that USP18 had this effect by inhibiting a protein called tumor necrosis factor (TNF), which allows the bacteria to reproduce. Disruption of USP18 had an antimicrobial effect; TNF function was restored and it encouraged the creation of reactive oxygen species, which can destroy bacteria.
"Our results were unexpected because the absence of USP18 augments type 1 interferon signaling, which, if the current thinking is correct, should promote rather than prevent bacterial infection," said Teijaro.
The researchers suggest that this work could open up new therapeutic avenues for bacterial and viral infections.
This is an investigation of basic processes in biology, but Teijaro noted that it provides insight into fundamental parts of the immune system, while offering new therapeutic opportunities. If USP18 function can be inhibited at the right time, it may boost the effectiveness of our natural interferons to fight microbial infections successfully. Learn more about how the immune system works from the video.
"One of our goals going forward is to test this therapeutically," said Teijaro. "We also want to expand our investigation to understand the role of USP18 in secondary bacterial pneumonia and tuberculosis infections."
There may be an important advantage to developing drugs that act upon USP18, Shaabani added. "Therapies targeting USP18 would also have the advantage of targeting the host, and not the bacteria directly, and therefore should be less susceptible to antibiotic resistance."