Strengthening the Body's Defenses Against Adenoviruses

Infection with adenoviruses can be life-threatening, especially for children after a stem cell transplant. Virologists from the Technical University of Munich (TUM) and the Helmholtz Zentrum München have now been able to show that an already approved drug from cancer treatment could help against the viral infection. Due to the special mechanism of action of the drug, the virus cannot develop defense strategies.

The so-called human adenoviruses cause, among other things, conjunctivitis, gastrointestinal complaints or pneumonia. In most cases, a disease develops in healthy adults without or with mild symptoms. "Every adult has usually gone through several adenovirus infections," explains Dr. Sabrina carpenter. She works at the Institute of Virology at TUM and the Helmholtz Zentrum München. The human viruses, of which there are currently more than 85 different variants, were previously not considered to be particularly dangerous.

No drug or vaccination available yet

However, people with a weakened immune system can experience severe and fatal courses of the infection. A disease is particularly dangerous for children after a stem cell transplant. In this case, the mortality in the infected patient is as high as 80 percent.

"Since 2006 it has also been known that adenovirus infections also occur in healthy people, which can cause severe pneumonia with fatal consequences," says Schreiner. So far, there is no drug that works specifically against adenoviruses. There are also no vaccinations for the normal population.

Protein complexes with antiviral function

Schreiner and her team investigate how the virus multiplies in the cell. They observed that the so-called PML core bodies, a complex of several proteins in the cell, change significantly when they are infected with adenoviruses.

The otherwise round structures dissolve and elongated fibrils develop. "It is believed that the PML core bodies have an antiviral function," explains Schreiner. "The viruses destroy the round structures of the protein complexes and then use this manipulation of the cell for their own reproduction."

The body's own defense is strengthened

The scientists noticed that the structures of the PML core bodies in cancer patients were also dissolved. However, if the patients were treated with ATO (arsenic trioxide), the round structures regressed. "ATO is a well-known active ingredient that has been approved and is currently used in the clinic for leukemia patients," explains Schreiner.

The researchers tested the effect of the drug on cell cultures infected with adenoviruses. In fact, the PML core bodies again formed round structures here, the virus concentration decreased. "So we can actually restore these endogenous antiviral factories that then fight the virus," says Schreiner.

Virus has no direct contact with the active ingredient

After the test in the laboratory, the drug will also be used in the next step in patients infected with adenoviruses. The virologists are in contact with pediatricians in clinics in Munich. Since the drug is already approved, it can be used directly for treatment. "Although it is an arsenic-containing compound, it does not have any cell-toxic side effects in the concentrations in which it is used and has already been approved," says Schreiner.

The peculiarity of this drug: It affects the cell's structures, not directly against the virus. "It is often the case that viruses develop resistance to drugs that attack them directly," explains Schreiner. “For example, they can mutate so that the drug no longer recognizes them. Since the virus has no direct interaction with the active ingredient in this case, it cannot develop any defense mechanisms. "

Reference
Samuel Hofmann, Julia Mai, Sawinee Masser, Peter Groitl, Alexander Herrmann, Thomas Sternsdorf, Ruth Brack-Werner, and Sabrina Schreiner: ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity, Advanced Science, February 2020. DOI: 10.1002 / advs.201902130.

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