How poxviruses multiply – sciencedaily

The last case of smallpox in the world occurred in Somalia in October 1977. In 1980, the World Health Organization (WHO) declared the eradication of smallpox. According to official sources, the virus still only exists today in two high-security laboratories in Russia and the United States, where it is used for research.

But while that means poxviruses are no longer an immediate threat to humans, this family of viruses is still of great interest to scientists. On the one hand, the modified strains are used in the treatment of cancer, and on the other hand, they have very intriguing multiplication properties.

Smallpox viruses build their own multiplication machine

While many viruses draw heavily on the biochemical resources of the host cell for their multiplication, poxviruses encode their own molecular machinery in their genome for this purpose. The important components of this machinery are two enzymes: DNA polymerase to multiply viral genes and RNA polymerase to transcribe viral genes into mRNA. RNA polymerase the vaccine The poxvirus strain, for example, is a large complex comprising 15 different protein subunits with different biochemical functions.

A team of researchers from the Biocentre of the Julius-Maximilian University in Würzburg (JMU) was able for the first time to observe the polymerase of the vaccine viruses doing their job at an atomic level. Before that, the team had already reported on the three-dimensional structure of atomic-resolved RNA polymerase. The group in charge of the work is led by Utz Fischer, who holds the JMU chair of the department of biochemistry I. The results of their work are now presented in a publication in the journal Structure of nature and molecular biology.

Three-dimensional structures at the atomic scale

“We mixed isolated RNA polymerase with a piece of DNA containing the promoter, ie the start signal for transcription of viral genes. The enzyme recognized precisely this element of DNA and began to produce mRNA, ”explains Julia Bartuli, in charge of biochemical work. of the study. In a next step, the samples were examined under a cryoelectron microscope, in cooperation with Bettina Böttcher from the Department of Biochemistry II. Based on the data collected, the scientists were able to reconstruct the three-dimensional structure of the sample down to the atomic scale, using modern computer methods.

They were excited about the end result of this long process: “A single sample that we examined under a microscope allowed us to reconstruct a total of six different polymerase complexes, which we were ultimately able to assign to individual phases of the transcription process. », Explains Clemens Grimm. , in charge of structural analysis in the Fischer department. “We can chain the individual images together like in a movie and thus represent the first phase of transcription with temporal resolution.”

Smallpox continues to be a threat to humans

But why bother to do research on poxviruses if the virus so dangerous for humans has already been eradicated? There are good reasons for this, answers Professor Fischer: “There is still no reliable cure for a smallpox infection, it can only be prevented by vaccination. If the still existing virus samples were to spread again, for example by a terrorist attack. , they would strike a population that has no vaccination. “

Another threat, which may be more real, are zoonotic diseases caused by animal-specific viruses that spread to humans, says biochemist Utz Fischer. For example, there are sporadic infections of humans with monkey pox, which can make infected people seriously ill. “If such a zoonosis picks up speed, adapting more to its human host and spreading from human to human, a dangerous epidemic could emerge,” he says.

Using computers to develop new drugs

Inhibitors of viral gene expression would therefore be highly relevant as antiviral drugs. Understanding the atomic structures of RNA polymerase in its various states now allows researchers a rational, structure-based computational approach to the development of such inhibitors. Such studies, the method of which differs fundamentally from the classical experimental procedure, are already well under way.

About smallpox viruses

People born before 1976 – at least in Germany – have a visible scar on their upper arm due to their vaccination against smallpox. Until that date, vaccination was compulsory in Germany. This vaccination is one of the most important successes in modern protection against infections. This made it possible to eradicate the deadly pathogen of smallpox. This pathogen, scientifically known as the variola virus, was the source of the smallpox epidemics that periodically struck mankind until the beginning of the 20th century and claimed the lives of millions of people.

The first forms of inoculation have been known since ancient times, when people put the scab from a healed smallpox blister into a small wound, hoping to prevent serious illness. This procedure called “variolation” was carried out in the 18th century in Europe, among others at the Juliusspital in Würzburg. The breakthrough in the fight against smallpox was made in 1976 by British physician Edward Jenner, who substituted the harmless pathogen of smallpox or smallpox for the much more dangerous smallpox virus.

The strain Jenner used made medical history with the name the vaccine. It lent its name to the routine immunization practices of today known as vaccinations. A global vaccination campaign using the vaccine strain ultimately led to the WHO declaration on the eradication of smallpox in 1980 – for the first time in human history an infectious disease had been defeated in the whole world.

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