{"id":44910,"date":"2021-12-02T12:11:04","date_gmt":"2021-12-02T11:11:04","guid":{"rendered":"https:\/\/www.embl.org\/news\/?p=44910"},"modified":"2024-08-29T14:08:15","modified_gmt":"2024-08-29T12:08:15","slug":"wrangling-an-octopus-like-viral-replication-machine","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science\/wrangling-an-octopus-like-viral-replication-machine\/","title":{"rendered":"Wrangling an octopus-like viral replication machine"},"content":{"rendered":"\n<p>Endemic in Western African countries, Lassa virus is transmitted to humans through food or household items that are contaminated with the urine or faeces of <em>Mastomys<\/em> rats. Even though many people who become infected with Lassa virus are asymptomatic, one in five infections results in severe haemorrhagic disease, attacking vital organs like the liver, spleen, and kidneys.<\/p>\n\n\n\n<p>The World Health Organization (WHO) lists Lassa fever as a significant public health threat with high epidemic potential and no effective countermeasures. Lassa fever has no vaccine, and only one drug \u2013 a broad-spectrum antiviral called ribavirin, which has limited efficacy.<\/p>\n\n\n\n<p>Even though researchers are working on a vaccine, an effective antiviral is needed to reduce the number of severe cases and deaths. This is where structural biology can help.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Sharing expertise<\/strong><\/h2>\n\n\n\n<p>To understand the intricate mechanism of viral replication, structural biologists focus on a key component: the viral polymerase. In an infected cell, this enzyme replicates the virus\u2019s genetic information. The genome copies are then packaged into new virions, which escape the cell and can infect a new host. Determining the polymerase structure helps researchers to understand how a virus replicates, giving them important insight into how to design drugs that can stop the infection.<\/p>\n\n\n\n<p>Stephen Cusack, head of EMBL Grenoble, focuses his group\u2019s research on the polymerase of several human pathogenic viruses, particularly influenza virus. Because influenza and Lassa viruses are from the same family \u2013 both segmented negative-strand RNA viruses \u2013 Cusack\u2019s group started collaborating on Lassa virus several years ago with Maria Rosenthal and Stephan G\u00fcnther from the Bernhard Nocht Institute for Tropical Medicine (BNITM) in Hamburg.<\/p>\n\n\n\n<p>\u201cStephen Cusack was at the forefront of research on influenza and ahead of the field with respect to bunyaviruses and arenaviruses,\u201d said G\u00fcnther, the head of the virology department at BNITM. \u201cWe thought it was excellent synergy because he already had a lot of technological knowledge we could transfer to the Lassa polymerase.\u201d<\/p>\n\n\n\n<p>The Lassa polymerase has characteristics that complicate the process of determining its structure, which Rosenthal, a BNITM structural biologist and group leader, had tried to obtain for several years. \u201cAfter a long testing of other systems, I went to Grenoble to test the system developed by Imre Berger (an EMBL Grenoble alumnus), and applied by the Cusack group to influenza. We got very good expression of the protein,\u201d Rosenthal said.<\/p>\n\n\n\n<p>The polymerase also has a peculiar architecture with a core and flexible outer components. \u201cWe call the Lassa virus polymerase an \u2018octopus\u2019 because it\u2019s like it has arms floating around, which makes it very hard to catch in one position,\u201d said Tomas Kouba, a postdoc in the Cusack Group.<\/p>\n\n\n\n<p>Macromolecular crystallography \u2013 an imaging technique commonly used in structural biology \u2013 couldn\u2019t be used to observe the Lassa polymerase, because the protein moved too much to capture all the arms. Cryo-electron microscopy (cryo-EM) offered the solution as it enables snapshots of the protein to be taken in different functional states.<\/p>\n\n\n\n<p>&#8220;We applied to Lassa the techniques that Kouba and Joanna Wandzik (a former EMBL PhD student) developed to visualise influenza polymerase in action,&#8221; Cusack explained. &#8221; We used cryo-EM facilities both in Grenoble and at the Centre for Structural Systems Biology [CSSB] at the University of Hamburg.\u201d<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Promising structures<\/strong><\/h2>\n\n\n\n<p>This collaboration between researchers from EMBL Grenoble, BNITM, and Kay Gr\u00fcnewald\u2019s lab at the CSSB resulted in a paper <a href=\"https:\/\/doi.org\/10.1038\/s41467-021-27305-5\" target=\"_blank\" rel=\"noreferrer noopener\">recently published in <em>Nature Communications<\/em><\/a>. It details nine structures of the Lassa viral polymerase in different functional configurations.<\/p>\n\n\n\n<p>\u201cWhen you observe this \u2018octopus\u2019, you also want to see how it behaves, how it moves its arms to eat or catch something,\u201d explained Kouba, one of the paper\u2019s three principal authors.<\/p>\n\n\n\n<p>\u201cThe power of cryo-EM is that you take millions of pictures of the protein. Then you can sort them into several boxes: one box with an arm up, and then one box with the arm down,\u201d Rosenthal added. \u201cIn the end, you have more highly resolved images of octopus arms in a variety of positions, so you can model them.\u201d<\/p>\n\n\n\n<p>These studies provide crucial insights into the Lassa virus, which has only four different viral proteins \u2013 very few compared to other viruses, such as herpes or SARS-CoV-2, which have dozens of components. The proteins make up for their small number by assuming multiple functions, like a Swiss Army knife. The researchers could, for example, visualise polymerase activity and propose how to block viral replication.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>One Health: preparedness<\/strong><\/h2>\n\n\n\n<p>The collaboration also explores other segmented negative-strand RNA viruses on WHO\u2019s priority list. This includes pathogens causing certain insect-borne viral diseases whose geographical spread may be affected by climate change.<\/p>\n\n\n\n<p>Formerly located mostly in tropical areas, these viruses are extending their range. This is already the case for tick-borne Crimean-Congo haemorrhagic fever virus, which has spread into southern Europe, or mosquito-borne Rift Valley fever, which is expected to spread.<\/p>\n\n\n\n<p>Even though these viruses differ significantly in many respects, their polymerases are closely related, and identifying similarities between them could help develop a broad-spectrum antiviral to tackle them all.<\/p>\n\n\n\n<p>\u201cStructural biology is important to understand what we are actually looking at,\u201d Rosenthal said. \u201cHow could you win a fight if you don\u2019t really know who you\u2019re fighting? If we know how these viruses work, then we have more ideas on how to tackle them.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"<p>EMBL structural biology is part of an international collaboration addressing zoonotic disease caused by Lassa virus.<\/p>\n","protected":false},"author":104,"featured_media":44918,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[2,17591],"tags":[474,17279,335,37,3684,11062,35,3686],"embl_taxonomy":[9792],"class_list":["post-44910","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","category-science-technology","tag-collaboration","tag-cryo-electron-microscopy","tag-cusack","tag-grenoble","tag-infection-biology","tag-one-health","tag-structural-biology","tag-virology","embl_taxonomy-embl-grenoble"],"acf":{"featured":true,"show_featured_image":false,"field_target_display":"","article_intro":"<p>EMBL structural biology is part of an international collaboration addressing zoonotic disease caused by Lassa virus<\/p>\n","related_links":[{"link_description":"Cusack group","link_url":"https:\/\/www.embl.org\/groups\/cusack\/"},{"link_description":"","link_url":""}],"source_article":[{"publication_title":"Conformational changes in Lassa virus L protein associated with promoted binding and RNA synthesis activity","publication_link":{"title":"","url":"https:\/\/doi.org\/10.1038\/s41467-021-27305-5","target":"_blank"},"publication_authors":"Kouba T., Vogel D., Thorkelsson S. R., et al.","publication_source":"Nature Communications","publication_date":"2 December 2021","publication_doi":"10.1038\/s41467-021-27305-5"}],"in_this_article":false,"press_contact":"None","vf_locked":false,"field_article_language":{"value":"english","label":"English"},"article_translations":false,"languages":""},"embl_taxonomy_terms":[{"uuid":"a:3:{i:0;s:36:\"b14d3f13-5670-44fb-8970-e54dfd9c921a\";i:1;s:36:\"89e00fee-87f4-482e-a801-4c3548bb6a58\";i:2;s:36:\"8f81131e-d37c-470c-848f-618fce652295\";}","parents":[],"name":["EMBL Grenoble"],"slug":"embl-grenoble","description":"Where &gt; All EMBL sites &gt; EMBL Grenoble"}],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.2 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Wrangling an octopus-like viral replication machine | EMBL<\/title>\n<meta name=\"description\" content=\"EMBL structural biology is part of an international collaboration addressing zoonotic disease caused by Lassa virus.\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.embl.org\/news\/science\/wrangling-an-octopus-like-viral-replication-machine\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Wrangling an octopus-like viral replication machine | EMBL\" \/>\n<meta property=\"og:description\" content=\"EMBL structural biology is part of an international collaboration addressing zoonotic disease caused by Lassa virus.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.embl.org\/news\/science\/wrangling-an-octopus-like-viral-replication-machine\/\" \/>\n<meta property=\"og:site_name\" content=\"EMBL\" \/>\n<meta property=\"article:publisher\" content=\"https:\/\/www.facebook.com\/embl.org\/\" \/>\n<meta property=\"article:published_time\" content=\"2021-12-02T11:11:04+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-08-29T12:08:15+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2021\/11\/Visuel-Lassa-virus_1000x600.png\" \/>\n\t<meta property=\"og:image:width\" content=\"1000\" \/>\n\t<meta property=\"og:image:height\" content=\"600\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/png\" \/>\n<meta name=\"author\" content=\"Myl\u00e8ne Andr\u00e9\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:creator\" content=\"@embl\" \/>\n<meta name=\"twitter:site\" content=\"@embl\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Myl\u00e8ne Andr\u00e9\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"5 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"NewsArticle\",\"@id\":\"https:\/\/www.embl.org\/news\/science\/wrangling-an-octopus-like-viral-replication-machine\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/wrangling-an-octopus-like-viral-replication-machine\/\"},\"author\":{\"name\":\"Myl\u00e8ne Andr\u00e9\",\"@id\":\"https:\/\/www.embl.org\/news\/#\/schema\/person\/845a38992ad0698d457ec1dd32d13c79\"},\"headline\":\"Wrangling an octopus-like viral replication machine\",\"datePublished\":\"2021-12-02T11:11:04+00:00\",\"dateModified\":\"2024-08-29T12:08:15+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/wrangling-an-octopus-like-viral-replication-machine\/\"},\"wordCount\":892,\"publisher\":{\"@id\":\"https:\/\/www.embl.org\/news\/#organization\"},\"image\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/wrangling-an-octopus-like-viral-replication-machine\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2021\/11\/Visuel-Lassa-virus_1000x600.png\",\"keywords\":[\"collaboration\",\"cryo-electron microscopy\",\"cusack\",\"grenoble\",\"infection biology\",\"one health\",\"structural biology\",\"virology\"],\"articleSection\":[\"Science\",\"Science &amp; 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