How poxviruses multiply

Date:
September 23, 2021
Source:
University of Wu"rzburg
Summary:
Poxviruses have found a unique way of translating their genes
into proteins in the infected organism. Scientists of the have
been able to gain atomic-level insights into the functioning of
the molecular machinery involved in the process.



FULL STORY ==========================================================================
The last case of smallpox worldwide occurred in Somalia in October
1977. In 1980, the World Health Organization (WHO) declared the
eradication of the smallpox. According to official sources, the virus
continues to exist today only in two high-security laboratories in Russia
and the USA, where it is used for research purposes.


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

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

A team of researchers from the Biocenter of the Julius-Maximilian's
University of Wu"rzburg (JMU) has now for the first time been able to
watch the polymerase of vacciniaviruses doing their work at an atomic
level. Before that, the team had already reported on three-dimensional structure of the RNA polymerase at atomic resolution. The group in
charge of the work is led by Utz Fischer, who holds the JMU's Chair of
the Department of Biochemistry I. The results of their work have now
been presented in a publication in the journal Nature Structure and
Molecular Biology.

Three-dimensional structures on an atomic scale "We have mixed isolated
RNA polymerase with a piece of DNA containing the promoter, i.e. the
start signal for the transcription of viral genes. The enzyme recognized precisely this DNA element and started producing mRNA," explains Julia
Bartuli, in charge of the biochemical work of the study. In a next step,
the samples were examined in the cryo-electron microscope, in cooperation
with Bettina Bo"ttcher from the Department of Biochemistry II. On the
basis of the data collected, the scientists were able to reconstruct
the three-dimensional structure of the sample down to the atomic scale,
using modern computerized methods.



==========================================================================
They were enthusiastic about the final result of this lengthy process:
"One single sample we examined in the microscope allowed us to reconstruct
a total of six different polymerase complexes, which we could finally
allocate to individual phases of the transcription process," says Clemens Grimm, in charge of structural analysis in Fischer's department. "We can
string the individual pictures together as in a movie and thus represent
the early transcription phase with time resolution." Smallpox continue
to be a threat to humans But why bother to do research on poxviruses if
the virus that is so dangerous to humans is eradicated already? There
are good reasons for this, replies Professor Fischer: "There is still
no reliable cure for a smallpox infection, it can only be prevented by a vaccination. If the still existing virus samples were to be spread again,
for example by a terrorist attack, they would hit a population that has
no immunization." Another threat, which may be more real, are zoonotic diseases caused by animal- specific viruses jumping to humans, explains biochemist Utz Fischer. For example, there are sporadic infections of
humans by monkeypox, which can make the infected persons severely ill. "If
such a zoonotic disease picks up speed, by further adaption to its human
host and human-to-human transmission, 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 different states allows researchers now a rational, structure-based computer approach to the development of such inhibitors. Such studies, which are fundamentally
different in method from the classic experimental procedure, are already
well underway.



========================================================================== About Smallpox Viruses People born before 1976 -- in Germany at any
rate -- bear on their upper arm a visible scar from their smallpox
vaccination. Up to that date vaccination was mandatory in Germany. This vaccination is among the most prominent successes of modern infection protection. It resulted in the eradication of the deadly smallpox
pathogen. This pathogen, scientifically known as variola virus, had been
the cause of smallpox epidemics that scourged humankind periodically until
well into the 20th century, and took the lives of millions of people.

Early forms of an inoculation of sorts have been known since antiquity,
when people introduced the scab of a healed smallpox blister into a small wound, hoping to thus prevent a severe illness. This procedure called "variolation" was performed in the 18th century in Europe, among other
places at the Juliusspital in Wu"rzburg. The breakthrough in the fight
against smallpox was achieved in 1976 by the British physician Edward
Jenner, who substituted the harmless horsepox or cowpox pathogen for
the much more dangerous smallpox virus.

The strain used by Jenner has gone down in medical history with the name vaccinia. It has lent its name to today's common immunization practices
known as vaccinations. A global vaccination campaign using the vaccinia
strain ultimately led to the WHO's declaration about the eradication of smallpox in 1980 -- for the first time in the history of humankind an infectious disease had been defeated world-wide.

========================================================================== Story Source: Materials provided by University_of_Wu"rzburg. Original
written by Gunnar Bartsch. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Grimm, C., Bartuli, J., Boettcher, B. et al. Structural basis of the
complete poxvirus transcription initiation process. Nat Struct
Mol Biol, 2021 DOI: 10.1038/s41594-021-00655-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210923115553.htm

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