More than 70% of winter bronchiolitis cases in young children are caused by respiratory syncytial virus (RSV). Scientists believe that all children will have been infected by the virus before the age of three, most frequently in epidemics in child care centres, for instance. A third of them will develop lower respiratory tract infections, with half of these cases requiring hospitalization. In adults, the disease is marked by flu-like symptoms or even pneumonia, which may prove fatal in elderly or immunocompromised patients. Owing to the number of consultations and hospitalizations it causes, RSV is a real public health problem. Despite long-standing efforts by the scientific community, no human vaccine currently exists. Moreover, available treatment is relatively ineffectual. Human RSV’s counterpart in bovines is a major cause of respiratory problems in calves. Disease severity and complications are similar for both the human and bovine forms of the virus, and require more basic research that will then serve as the backbone for developing prevention and treatment options for humans and disease control options in cattle.
RSV is an RNA virus that stores its genetic material in a single strand of RNA, unlike most other organisms, which carry their genetic material in a double-stranded DNA molecule. This RNA is enclosed in a nucleoprotein. When the virus penetrates the lung’s cells, it takes over the host’s cell machinery in order to produce a large number of virus copies that can then go on to infect other cells or be passed to other individuals. The nucleoprotein protects viral RNA from the host’s immune defenses while it is in the host cell, and helps in virus proliferation by presenting the RNA to the viral enzyme that copies it.
Researchers crystallised the protein/RNA complex in order to study its function. By examining the crystals using a synchrotron, a machine that produces extremely powerful Xrays, and processing the data using computers, they were able to build a high-resolution image of the complex’s structure. This detailed image shows how the nucleoproteins join up with the help of “arms” to form a chain - somewhat like rugby players in a scrum - along the RNA strand. Each nucleoprotein is made up of two domains that close around the RNA like tongs, and are separated by a flexible junction. The scientists hypothesised that during viral multiplication, the tongs open to let the enzyme through so that it can read the genetic information contained in the RNA sequence. Viral RNA would thus be always protected inside the complex.
The key role played by the nucleoprotein in virus multiplication makes it an ideal target for the development of drugs for the disease, as treatment options are sorely lacking. Since the nucleoprotein must open up to provide access to genetic information, a molecule that would block this opening would be a treatment of choice. Such molecules would interrupt virus replication and dissemination in the respiratory tract. The detailed image of its three-dimensional structure, for which a patent application has been filed, will help in the development of potential therapeutic agents, by allowing the creation of designer molecules that can inhibit viral replication. This research shows how basic research on the structure of a virus can have far-reaching medical and veterinary applications.
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Three-dimensional structure of the respiratory syncytial virus nucleoprotein. The virus genome is composed of an RNA molecule (black and turquoise) covered by a two-lobed nucleoprotein (red and yellow) that closes around the RNA like a clamp. Two arms (dark blue) allow the nucleoprotein to interact with neighbouring molecules and form a continuous chain, hiding and protecting the RNA.
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Source
X-ray structure of a nucleocapsid-like Nucleoprotein-RNA complex of Respiratory Syncytial
Virus.
SCIENCE, 27 November 2009, vol. 326, pp. 1279-1283.
Rajiv G. Tawar(1), Stéphane Duquerroy(1,2), Clemens Vonrhein(3), Paloma F. Varela(1), Laurence Damier- Piolle(1), Nathalie Castagné(4), Kirsty MacLellan(5), Hugues Bedouelle(6), Gérard Bricogne(3), David Bhella(4), Jean-François Eléouët(4) and Félix A. Rey(1).
(1) Institut Pasteur, Unité de Virologie structurale, département de Virologie et CNRS URA 3015, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
(2) Université Paris-Sud 11, Faculté des Sciences d’Orsay, 91405 Orsay Cedex, France.
(3) Global Phasing Ltd, Sheraton House, Castle Park, Cambridge CB3 0AX United Kingdom.
(4) INRA, Unité de Virologie et immunologie moléculaires, Domaine du Vilvert, 78350 Jouy-en-Josas,
France.
(5) MRC Virology Unit, University of Glasgow, Church Street, Glasgow, G11 5JR, United Kingdom.
(6) Institut Pasteur, CNRS URA 3012, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
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