Researchers from EMBL Grenoble have, for the first time, observed different functional states of the influenza virus polymerase as it is actively transcribing. These results, published in Nature Structural & Molecular Biology, provide valuable information for the next generation of anti-influenza drugs.<\/p>\n\n\n\n
When a virus infects and enters a host cell, the genomic material in the virus is both replicated to produce multiple copies of itself and transcribed into viral messenger RNA (mRNA). The viral mRNA can be read by the host cell\u2019s protein production machinery, tricking it into making viral proteins. The viral proteins package the copies of the viral genome to make progeny viruses that are released from the cell to infect new hosts. An enzyme called a polymerase is responsible for both the transcription and replication of the viral genome and is therefore crucial to the successful propagation of the virus. The influenza virus, with genomic material made of RNA rather than DNA, is no exception to this modus operandi.<\/p>\n\n\n\n
\u201cStudying and understanding the unique mechanisms of transcription and replication used by influenza virus is essential to fight its spread,\u201d explains EMBL group leader Stephen Cusack.<\/p>\n\n\n\n
Stephen Cusack and his research group at EMBL Grenoble started to work on influenza polymerase more than 20 years ago. In 2014, the group published the first crystal structures of the complete polymerase machine. However, attempts to structurally characterise the different states of actively transcribing influenza polymerase have so far been unsuccessful.<\/p>\n\n\n\n
\u201cAll studies so far have looked at the resting structure of the polymerase machine; we\u2019ve never observed it actually doing anything,\u201d says Tomas Kouba, a postdoc in the group who, together with Petra Drncov\u00e1, carried out much of the work.<\/p>\n\n\n\n
Using X-ray crystallography and cryo-electron microscopy, both performed on state-of-the-art equipment at the European Synchrotron Radiation Facility in Grenoble, the group were able to determine, for the first time, atomic-resolution structures of different functional states of the influenza polymerase as it is actively transcribing genomic RNA into mRNA. In particular, it provides the first characterisation of the movements of the polymerase during the so-called nucleotide addition cycle, whereby each successive nucleotide is added to the growing mRNA chain.<\/p>\n\n\n\n
Despite its familiarity, the influenza virus \u2013 some strains of which are among the top ten most dangerous viruses in the world \u2013 is far from being well understood. Up to 500,000 people worldwide die from influenza each year, according to the World Health Organization, with potentially much higher mortality rates when a new pandemic flu strain emerges. Vaccination is not always effective and anti-influenza drugs are needed as a complementary treatment option.<\/p>\n\n\n\n
As the viral polymerase is essential for the replication of the flu virus, it is a prime target for the development of new anti-influenza drugs. As such, the results gained by the EMBL group give new insights to help design the next generation of anti-influenza drugs. The advantage of drugs that stop the polymerase functioning is that it is much less likely that the virus will mutate in a way that would render the drug useless.<\/p>\n\n\n\n
\u201cOur results contribute the first snapshots of a movie that will show the complete transcription cycle of influenza polymerase from initiation to termination,\u201d explains Cusack. The group will continue to use the powerful technique of cryo-electron microscopy to fill in the missing steps.<\/p>\n\n\n\n
Les chercheurs de l’EMBL Grenoble ont, pour la premi\u00e8re fois, observ\u00e9 diff\u00e9rents \u00e9tats fonctionnels de la polym\u00e9rase du virus influenza en cours de transcription active. Ces r\u00e9sultats, publi\u00e9s dans Nature Structural & Molecular Biology, fournissent des informations pr\u00e9cieuses pour la prochaine g\u00e9n\u00e9ration de traitements contre la grippe.<\/p>\n\n\n\n
Lorsqu’un virus infecte et p\u00e9n\u00e8tre dans une cellule h\u00f4te, le mat\u00e9riel g\u00e9nomique du virus est \u00e0 la fois reproduit en de multiples copies de lui-m\u00eame et transcrit en ARN messager viral (ARNm). L’ARNm viral peut \u00eatre lu par les m\u00e9canismes de production de prot\u00e9ines de l’h\u00f4te, ce qui les incite \u00e0 fabriquer des prot\u00e9ines virales. Les prot\u00e9ines virales conditionnent les copies du g\u00e9nome pour en faire des virus descendants qui sont lib\u00e9r\u00e9s de la cellule pour infecter de nouveaux h\u00f4tes. Une enzyme m\u00e9canique appel\u00e9e polym\u00e9rase est responsable \u00e0 la fois de la transcription et de la r\u00e9plication du g\u00e9nome viral et est donc essentielle \u00e0 la propagation du virus. Le virus de la grippe, dont le mat\u00e9riel g\u00e9nomique est constitu\u00e9 d’ARN plut\u00f4t que d’ADN, ne fait pas exception \u00e0 ce mode de fonctionnement.
\u00ab Il est essentiel d\u2019\u00e9tudier et de comprendre les m\u00e9canismes uniques de transcription et de r\u00e9plication utilis\u00e9s par le virus de la grippe pour lutter contre sa propagation \u00bb, explique Stephen Cusack, responsable de l’\u00e9quipe.<\/p>\n\n\n\n
Stephen Cusack et son \u00e9quipe de l’EMBL Grenoble ont commenc\u00e9 \u00e0 travailler sur la polym\u00e9rase grippale il y a plus de 20 ans. En 2014, le groupe a publi\u00e9 les premi\u00e8res structures cristallines du m\u00e9canisme complet de polym\u00e9rase. Cependant, jusqu’\u00e0 pr\u00e9sent, les tentatives de caract\u00e9risation structurelle des diff\u00e9rentes \u00e9tapes de la transcription active de la polym\u00e9rase grippale ont \u00e9chou\u00e9.
\u00ab Jusqu’\u00e0 pr\u00e9sent, toutes les \u00e9tudes ont examin\u00e9 la structure du m\u00e9canisme de polym\u00e9rase au repos ; nous ne l’avons jamais observ\u00e9e en train de faire quoi que ce soit \u00bb, explique Tomas Kouba, chercheur postdoctoral qui, avec Petra Drncov\u00e1, a effectu\u00e9 une grande partie du travail.<\/p>\n\n\n\n
Gr\u00e2ce \u00e0 la cristallographie aux rayons X et \u00e0 la cryo-microscopie \u00e9lectronique, toutes deux r\u00e9alis\u00e9es sur des \u00e9quipements de pointe \u00e0 l’ESRF de Grenoble, l’\u00e9quipe a pu d\u00e9terminer, pour la premi\u00e8re fois, les structures de r\u00e9solution atomique de diff\u00e9rents \u00e9tats fonctionnels de la polym\u00e9rase de la grippe, qui transcrivent activement l’ARN g\u00e9nomique en ARNm. Il fournit plus particuli\u00e8rement la premi\u00e8re caract\u00e9risation des mouvements de la polym\u00e9rase au cours du cycle d’addition nucl\u00e9otidique, chaque nucl\u00e9otide successif \u00e9tant ajout\u00e9 \u00e0 la cha\u00eene croissante de l’ARNm.<\/p>\n\n\n\n
Malgr\u00e9 son caract\u00e8re familier, le virus de la grippe – dont certaines souches figurent parmi les dix virus les plus dangereux au monde – est loin d’\u00eatre bien compris. Selon l’OMS, jusqu’\u00e0 500 000 personnes dans le monde meurent chaque ann\u00e9e de cette maladie, avec des taux de mortalit\u00e9 potentiellement beaucoup plus \u00e9lev\u00e9s lorsqu’une nouvelle souche pand\u00e9mique de grippe appara\u00eet. La vaccination n’est pas toujours efficace et les traitements contre la grippe sont n\u00e9cessaires comme option th\u00e9rapeutique compl\u00e9mentaire.
\u00c9tant donn\u00e9 que la polym\u00e9rase est essentielle \u00e0 la r\u00e9plication du virus de la grippe, elle constitue une cible de choix pour le d\u00e9veloppement de nouveaux m\u00e9dicaments antigrippaux. Ainsi, les r\u00e9sultats obtenus par l’\u00e9quipe de l’EMBL fournissent de nouvelles informations pour aider \u00e0 concevoir la prochaine g\u00e9n\u00e9ration de traitements antigrippaux. Les traitements qui emp\u00eachent le fonctionnement de la polym\u00e9rase ont l\u2019avantage de r\u00e9duire la probabilit\u00e9 que le virus ne mute d’une mani\u00e8re qui rendrait le m\u00e9dicament inutile.
\u00ab Nos r\u00e9sultats fournissent les premi\u00e8res images instantan\u00e9es d’un film qui montrera le cycle complet de transcription de la polym\u00e9rase grippale, du d\u00e9but \u00e0 la fin \u00bb, explique M. Cusack. L’\u00e9quipe continuera d’utiliser la nouvelle technique performante de la cryo-microscopie \u00e9lectronique pour compl\u00e9ter les \u00e9tapes manquantes.<\/p>\n","protected":false},"excerpt":{"rendered":"
Snapshots of the flu virus replication machine in action<\/p>\n","protected":false},"author":71,"featured_media":15948,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[2,17591],"tags":[335,981,656,37,655,657,1748],"embl_taxonomy":[],"class_list":["post-15945","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","category-science-technology","tag-cusack","tag-drug","tag-flu","tag-grenoble","tag-influenza","tag-polymerase","tag-press-release"],"acf":{"article_intro":"
Snapshots of the flu virus replication machine in action<\/p>\n","related_links":[{"link_description":"","link_url":""}],"article_sources":[{"source_description":"
Kouba, T, Drncov\u00e1, P, and Cusack, S. Structural snapshots of actively transcribing influenza polymerase. Nature Structural & Molecular Biology<\/em>, published online 3 June 2019.
\nDOI: 10.1038\/s41594-019-0232-z<\/p>\n","source_link_url":"https:\/\/www.nature.com\/articles\/s41594-019-0232-z"}],"vf_locked":false,"featured":false,"color":"#007B53","show_featured_image":false,"in_this_article":false,"youtube_url":"","mp4_url":"","video_caption":"","translations":[{"translation_language":"French","translation_anchor":"#a1"}],"press_contact":"EMBL Generic","field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"source_article":false,"article_translations":false,"languages":""},"embl_taxonomy_terms":[],"yoast_head":"\n