In 1918, 50 million people died during a worldwide influenza pandemic caused by mutation of a bird-specific strain of the influenza virus. Recently H5N1, another highly infectious avian strain has caused outbreaks of bird flu around the world. There is great concern that this virus might also mutate to allow human-to-human transmission and cause another catastrophic pandemic.
Specific mutations in a viral protein, the polymerase, contribute to the ability of the bird virus to jump the species barrier to humans. Researchers from the European Molecular Biology Laboratory (EMBL) in Grenoble and Heidelberg, the Institut de Biologie Structurale (IBS) and the Unit of Virus Host Cell Interactions (UVHCI)*, both in Grenoble, have now produced the first 3-dimensional image of part of this key protein. The study, which is published in the current issue of Nature Structural and Molecular Biology, investigates the structure and function of the protein and sheds light on how polymerase mutations contribute to transmission of avian flu to humans.
Upon infection the influenza virus starts multiplying in the cells of an infected host. The polymerase is crucial in this process because it copies the viral genome and directs the production of its proteins. Interfering with polymerase function would prevent the virus replicating, thereby reducing the spread of the virus and the severity of the infection.
“For many years scientists have tried to understand the flu polymerase and to look for weak points that could be targeted by drugs,” says Darren Hart, whose team participated in the research at EMBL Grenoble. “But no one could get enough protein to analyse its structure. We developed a way to use robots to screen tens of thousands of experimental conditions and discovered a piece of the influenza polymerase that we could work with. It is a small part of the entire protein, but it provides interesting insights into how the protein works and how mutations may affect host range.”
Together with scientists at the IBS they visualized the atomic structure of the protein and discovered a previously overlooked signal that labels it for transport to the human nucleus where the genetic material of the virus is replicated. Cell microscopy studies at EMBL Heidelberg revealed that the human nuclear transport protein, importin alpha, recognises this signal and shuttles the polymerase into the nucleus. To find out how the polymerase and importin interact, Stephen Cusack, head of EMBL Grenoble, and collaborators at the UVHCI, used the high intensity X-ray source of the European Synchrotron Radiation Facility to generate a high-resolution image of the two proteins interacting with each other. The image revealed that mutations known to play a role in the transmission of avian influenza virus to mammals were located within, or close to, this site of interaction. This suggests that mutations may affect the efficiency of nuclear transport and through this the ability of the virus to replicate in different species.
“Interfering with polymerase function could provide new ways to treat or prevent flu,” says Cusack, “but this will require a detailed picture of the rest of the polymerase. This is what we are aiming for in our new FLUPOL project. In a joint effort with other European laboratories, and with financial support by the European Commission, we will explore both structure and function of this key drug target and try to characterise other mutations implicated in bird-to-human transmission.”
* The Unit of Virus Host Cell Interactions is a collaboration of the Centre National de la Recherche Scientifique (CNRS), the Université Joseph-Fourier in Grenoble and EMBL.
Anna-Lynn Wegener | alfa
What the world's tiniest 'monster truck' reveals
23.08.2017 | American Chemical Society
Treating arthritis with algae
23.08.2017 | Empa - Eidgenössische Materialprüfungs- und Forschungsanstalt
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
23.08.2017 | Life Sciences
23.08.2017 | Life Sciences
23.08.2017 | Physics and Astronomy