{"71010":{"#nid":"71010","#data":{"type":"news","title":"Study Reveals How Multiple Viruses Can Determine Bacterial Cell Fate","body":[{"value":"\u003Cp\u003EA new study suggests that bacteria-infecting viruses - called phages - can make collective decisions about whether to kill host cells immediately after infection or enter a latent state to remain within the host cell.\u003C\/p\u003E\n\u003Cp\u003EThe research, published in the September 15 issue of the \u003Cem\u003EBiophysical Journal\u003C\/em\u003E, shows that when multiple viruses infect a cell, this increases the number of viral genomes and therefore the overall level of viral gene expression. Changes in viral gene expression can have a dramatic nonlinear effect on gene networks that control whether viruses burst out of the host cell or enter a latent state.\n\u003C\/p\u003E\n\u003Cp\u003E\u0022What has confounded the virology community for quite some time is the observation that the cell fate of a bacteria infected by a single virus can be dramatically different than that infected by two viruses,\u0022 said Joshua Weitz, an assistant professor in the School of Biology at the Georgia Institute of Technology. \u0022Our study suggests that viruses can collectively decide whether or not to kill a host, and that individual viruses \u0027talk\u0027 to each other as a result of interactions between viral genomes and viral proteins they direct the infected host to produce.\u0022\n\u003C\/p\u003E\n\u003Cp\u003ETo study viral infections, Weitz teamed with postdoctoral fellow Yuriy Mileyko, graduate student Richard Joh and Eberhard Voit, who is a professor in the Wallace H. Coulter Department of Biomedical Engineering, the David D. Flanagan Chair Georgia Research Alliance Eminent Scholar in Biological Systems and director of the new Integrative BioSystems Institute at Georgia Tech.\n\u003C\/p\u003E\n\u003Cp\u003ENearly all previous theoretical studies have claimed that switching between \u0027lysis\u0027 and \u0027latency\u0027 pathways depends on some change in environmental conditions or random chance. However, this new study suggests that the response to co-infection can be an evolvable feature of viral life history.\n\u003C\/p\u003E\n\u003Cp\u003EFor this study, the researchers analyzed the decision circuit that determines whether a virus initially chooses the pathway that kills the host cell - called the lytic pathway - or the pathway where it remains dormant inside the host cell - called the lysogenic pathway.\u003C\/p\u003E\n\u003Cp\u003EWhen the lytic pathway is selected, the virus utilizes bacterial resources to replicate and then destroys the host cell, releasing new viruses that can infect other cells. In contrast, in the lysogenic pathway, the viral genome inserts itself into the bacterial genome and replicates along with it, while repressing viral genes that lead to lysis. The virus remains dormant until host conditions change, which can result in a switch to the lytic pathway.\n\u003C\/p\u003E\n\u003Cp\u003EThe decision of the genetic circuit that controls whether a virus initially chooses lysis or lysogeny is not random. Instead, cell fate is controlled by the number of infecting viruses in a coordinated fashion, according to the new study, which was funded by the Defense Advanced Research Projects Agency, the National Science Foundation and the Burroughs Wellcome Fund.\n\u003C\/p\u003E\n\u003Cp\u003E\u0022In the case of perhaps the most extensively studied bacteriophage, lambda phage, experimental evidence indicates that a single infecting phage leads to host cell death and viral release, whereas if two or more phages infect a host the outcome is typically latency,\u0022 explained Weitz, who is a core member of the new Integrative BioSystems Institute at Georgia Tech. \u0022We wanted to know why two viruses would behave differently than a single virus, given that the infecting viruses possess the same genetic decision circuit.\u0022\n\u003C\/p\u003E\n\u003Cp\u003ETo find out, the researchers modeled the complex gene regulatory dynamics of the lysis-lysogeny switch for lambda phage. They tracked the dynamics of three key genes - \u003Cem\u003Ecro, cI and cII\u003C\/em\u003E - and their protein production. The decision circuit involved both negative and positive feedback loops, which responded differently to changes in the total number of viral genomes inside a cell. The positive feedback loop was linked to the lysogenic pathway and the negative feedback loop was linked to the lytic pathway.\n\u003C\/p\u003E\n\u003Cp\u003EWith a single virus, \u003Cem\u003Ecro\u003C\/em\u003E dominated and the lytic pathway prevailed. If the number of co-infecting viruses exceeded a certain threshold, the positive feedback loop associated with \u003Cem\u003EcI\u003C\/em\u003E dominated, turning the switch to the lysogenic pathway. The differences in bacterial cell fate were stark and hinged upon whether or not one or two viruses were inside a given cell. \u003C\/p\u003E\n\u003Cp\u003EThe researchers found that the \u003Cem\u003EcII\u003C\/em\u003E gene acted as the gate for the system. Increasing the number of viruses drove the dynamic level of \u003Cem\u003EcII\u003C\/em\u003E proteins past a critical point facilitating production of \u003Cem\u003EcI\u003C\/em\u003E proteins leading to the lysogenic pathway. \n\u003C\/p\u003E\n\u003Cp\u003E\u0022The decision circuit is a race between two pathways and in the case of a single virus, the outcome is biased toward lysis,\u0022 explained Weitz. \u0022In our model, when multiple viruses infect a given cell, the overall production of regulatory proteins increases. This transient increase is reinforced by a positive feedback loop in the latency pathway, permitting even higher production of lysogenic proteins, and ultimately the latent outcome.\u0022\n\u003C\/p\u003E\n\u003Cp\u003EThe central idea in the model proposed by Weitz and collaborators is that increases in the overall amount of viral proteins produced from multiple viral genomes can have a dramatic effect on the nonlinear gene networks that control cell fate. \n\u003C\/p\u003E\n\u003Cp\u003E\u0022Many questions still remain, including to what extent subsequent viruses can change the outcome of previously infected, but not yet committed, viruses, and to what extent microenvironments inside the host impact cell fate,\u0022 added Weitz. \u0022Nonetheless, this study proposes a mechanistic explanation to a long-standing paradox by showing that when multiple viruses infect a host cell, those viruses can make a collective decision rather than behaving as they would individually.\u0022\n\u003C\/p\u003E\n\u003Cp\u003E\u003Cstrong\u003EResearch News \u0026amp; Publications Office\u003Cbr \/\u003E\nGeorgia Institute of Technology\u003Cbr \/\u003E\n75 Fifth Street, N.W., Suite 100\u003Cbr \/\u003E\nAtlanta, Georgia  30308  USA\n\u003C\/strong\u003E\u003C\/p\u003E\n\u003Cp\u003EMedia Relations Contacts: Abby Vogel (404-385-3364); E-mail: (\u003Ca href=\u0022mailto:avogel@gatech.edu\u0022\u003Eavogel@gatech.edu\u003C\/a\u003E) or John Toon (404-894-6986); E-mail: (\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E).\n\u003C\/p\u003E\n\u003Cp\u003E\u003Cstrong\u003ETechnical Contact:\u003C\/strong\u003E Joshua Weitz (404-385-6169); E-mail: (\u003Ca href=\u0022mailto:jsweitz@gatech.edu\u0022\u003Ejsweitz@gatech.edu\u003C\/a\u003E).\n\u003C\/p\u003E\n\u003Cp\u003E\u003Cstrong\u003EWriter:\u003C\/strong\u003E Abby Vogel\n\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":[{"value":"Bacteria-infecting viruses make collective decisions about whether to kill host cell"}],"field_summary":[{"value":"A new study suggests that bacteria-infecting viruses - called phages - can make collective decisions about whether to kill host cells immediately after infection or enter a latent state to remain within the host cell.","format":"limited_html"}],"field_summary_sentence":[{"value":"Viruses coordinate to determine a bacterial cell\u0027s fate"}],"uid":"27206","created_gmt":"2008-09-15 00:00:00","changed_gmt":"2016-10-08 03:03:19","author":"Abby Vogel Robinson","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2008-09-15T00:00:00-04:00","iso_date":"2008-09-15T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"71011":{"id":"71011","type":"image","title":"Joshua Weitz","body":null,"created":"1449177338","gmt_created":"2015-12-03 21:15:38","changed":"1475894628","gmt_changed":"2016-10-08 02:43:48"},"71012":{"id":"71012","type":"image","title":"Weitz and collaborators","body":null,"created":"1449177338","gmt_created":"2015-12-03 21:15:38","changed":"1475894628","gmt_changed":"2016-10-08 02:43:48"},"71013":{"id":"71013","type":"image","title":"Joshua Weitz 2","body":null,"created":"1449177338","gmt_created":"2015-12-03 21:15:38","changed":"1475894628","gmt_changed":"2016-10-08 02:43:48"}},"media_ids":["71011","71012","71013"],"related_links":[{"url":"http:\/\/www.ibsi.gatech.edu\/","title":"Integrative BioSystems Institute"},{"url":"http:\/\/www.biology.gatech.edu\/","title":"School of Biology"},{"url":"http:\/\/www.bme.gatech.edu\/facultystaff\/faculty_record.php?id=81","title":"Eberhard Voit"},{"url":"http:\/\/www.biology.gatech.edu\/faculty\/joshua-weitz\/","title":"Joshua Weitz"},{"url":"http:\/\/dx.doi.org\/10.1529\/biophysj.108.133694","title":"Biophysical Journal article"}],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"154","name":"Environment"},{"id":"146","name":"Life Sciences and Biology"},{"id":"135","name":"Research"}],"keywords":[{"id":"7077","name":"bacteria"},{"id":"532","name":"cell"},{"id":"7232","name":"collective"},{"id":"3748","name":"communication"},{"id":"7233","name":"decision"},{"id":"7111","name":"dynamics"},{"id":"7239","name":"fate"},{"id":"1133","name":"genome"},{"id":"7231","name":"host"},{"id":"7234","name":"lysis"},{"id":"7235","name":"lysogeny"},{"id":"7236","name":"lytic"},{"id":"1385","name":"network"},{"id":"3003","name":"protein"},{"id":"7238","name":"regulatory"},{"id":"7237","name":"replicate"},{"id":"7230","name":"viral"},{"id":"4292","name":"virus"}],"core_research_areas":[],"news_room_topics":[],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cstrong\u003EAbby Robinson\u003C\/strong\u003E\u003Cbr \/\u003EResearch News and Publications\u003Cbr \/\u003E\u003Ca href=\u0022http:\/\/www.gatech.edu\/contact\/index.html?id=avogel6\u0022\u003EContact Abby Robinson\u003C\/a\u003E\u003Cbr \/\u003E\u003Cstrong\u003E404-385-3364\u003C\/strong\u003E","format":"limited_html"}],"email":["abby@innovate.gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}