If security signs were posted inside the cell, they wouldn’t display images of video cameras. Instead, they might warn would-be intruders—poxviruses, for instance—of DNA sensors. Unfortunately, such signs wouldn’t deter poxviruses, which brazenly replicate their large genomes in the cytosol while somehow remaining unseen.

Hoping to make sense of this security lapse, scientists from the Spanish National Research Council and the University of Surrey evaluated a DNA sensor called the cGAS-STING pathway. The scientists wanted to know how it could fail to detect viral DNA in the cytosol. Ideally, viral DNA should be recognized by cyclic GMP-AMP (cGAMP) synthase (cGAS), which should then activate innate immune responses via stimulator of interferon genes (STING).

Yet poxviruses manage to defeat the cGAS-STING pathway. How? According to the scientists, poxviruses make use of just one of their genes, viral Schlafen (vSlfn). Thanks to vSlfn, poxviruses such as cowpox and monkeypox, which can spread to humans, escape detection, replicate unmolested, and drive infections that can cause skin lesions, fever, swollen lymph nodes, and even death.

The scientists described the vSlfn gene’s function in a paper (“Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection”) that appeared in Science Advances. In this paper, the scientists presented evidence, from experiments in mice, that cGAS-STING activation is required to resist lethal poxvirus infection.

“We identified vSlfn as the main STING inhibitor, and ectromelia virus was severely attenuated in the absence of vSlfn,” the article’s authors wrote. “Both vSlfn-mediated virulence and STING inhibitory activity were mapped to the recently discovered poxin cGAMP nuclease domain.”

Ectromelia virus, a member of the poxvirus family that causes mousepox, resembles human smallpox. Ectromelia virus spreads through the lymphatic system of mice to vital organs, where massive replication of the virus takes place, resulting in the rapid death of the animal.

During their investigations, scientists found that vSlfn blocks the cellular response to the virus genome, essentially rendering the virus invisible to the immune system. Remarkably, disabling this one gene made the infection detectable, triggering a potent immune response that protected animals against doses one million times higher than the regular lethal quantity.

After vSlfn was removed, the scientists found that animals with the modified virus were protected from subcutaneous, respiratory, and intravenous infection. All these animals survived. The scientists also found that the protection was mediated by interferon, a known molecule with powerful antiviral properties, and natural killer cells, which play a major role in the host-rejection of virally infected cells.

Researchers believe that these findings will shed light into how we combat microbial infections and will improve the efficacy and safety of vaccines, anticancer agents, and gene therapies that are based on poxviruses.

“Viruses, although minuscule, are very complex agents with very sophisticated strategies contained in their genetic material,” noted Carlos Maluquer de Motes, PhD, one of the study’s corresponding authors and a senior lecturer in molecular virology at the University of Surrey. “But it is also this same genetic material that makes them vulnerable to cell recognition. The removal of vSlfn gene protected animals against mousepox, and we believe that we may see the same results for other poxviruses.

“Our findings reveal the importance of activating the molecules responsible for the detection of the genetic material of microbes in the fight against viruses. In addition, they also suggest that mimicking the action of vSlfn may be a valid strategy to prevent autoinflammatory and autoimmune diseases that are caused when the genetic material of cells is sensed by the immune system, promoting a reaction.”

The study’s other corresponding authors, Antonio Alcami, PhD, a researcher at the Spanish National Research Council, added, “Viral inhibition of DNA sensing prevents the induction of the type I IFN response and complements another viral mechanism to sequester type I IFN through the secretion of soluble IFN decoy receptors. This highlights the importance of the type I IFN response in the control of immunity.”

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