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Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways
The intracellular endosymbiotic bacterium Wolbachia can protect insects against viral infection, and is being introduced into mosquito populations in the wild to block the transmission of arboviruses that infect humans and are a major public health concern. To investigate the mechanisms underlying t...
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Published in: | PLoS pathogens 2016-04, Vol.12 (4), p.e1005536-e1005536 |
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creator | Rainey, Stephanie M Martinez, Julien McFarlane, Melanie Juneja, Punita Sarkies, Peter Lulla, Aleksei Schnettler, Esther Varjak, Margus Merits, Andres Miska, Eric A Jiggins, Francis M Kohl, Alain |
description | The intracellular endosymbiotic bacterium Wolbachia can protect insects against viral infection, and is being introduced into mosquito populations in the wild to block the transmission of arboviruses that infect humans and are a major public health concern. To investigate the mechanisms underlying this antiviral protection, we have developed a new model system combining Wolbachia-infected Drosophila melanogaster cell culture with the model mosquito-borne Semliki Forest virus (SFV; Togaviridae, Alphavirus). Wolbachia provides strong antiviral protection rapidly after infection, suggesting that an early stage post-infection is being blocked. Wolbachia does appear to have major effects on events distinct from entry, assembly or exit as it inhibits the replication of an SFV replicon transfected into the cells. Furthermore, it causes a far greater reduction in the expression of proteins from the 3' open reading frame than the 5' non-structural protein open reading frame, indicating that it is blocking the replication of viral RNA. Further to this separation of the replicase proteins and viral RNA in transreplication assays shows that uncoupling of viral RNA and replicase proteins does not overcome Wolbachia's antiviral activity. This further suggests that replicative processes are disrupted, such as translation or replication, by Wolbachia infection. This may occur by Wolbachia mounting an active antiviral response, but the virus did not cause any transcriptional response by the bacterium, suggesting that this is not the case. Host microRNAs (miRNAs) have been implicated in protection, but again we found that host cell miRNA expression was unaffected by the bacterium and neither do our findings suggest any involvement of the antiviral siRNA pathway. We conclude that Wolbachia may directly interfere with early events in virus replication such as translation of incoming viral RNA or RNA transcription, and this likely involves an intrinsic (as opposed to an induced) mechanism. |
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To investigate the mechanisms underlying this antiviral protection, we have developed a new model system combining Wolbachia-infected Drosophila melanogaster cell culture with the model mosquito-borne Semliki Forest virus (SFV; Togaviridae, Alphavirus). Wolbachia provides strong antiviral protection rapidly after infection, suggesting that an early stage post-infection is being blocked. Wolbachia does appear to have major effects on events distinct from entry, assembly or exit as it inhibits the replication of an SFV replicon transfected into the cells. Furthermore, it causes a far greater reduction in the expression of proteins from the 3' open reading frame than the 5' non-structural protein open reading frame, indicating that it is blocking the replication of viral RNA. Further to this separation of the replicase proteins and viral RNA in transreplication assays shows that uncoupling of viral RNA and replicase proteins does not overcome Wolbachia's antiviral activity. This further suggests that replicative processes are disrupted, such as translation or replication, by Wolbachia infection. This may occur by Wolbachia mounting an active antiviral response, but the virus did not cause any transcriptional response by the bacterium, suggesting that this is not the case. Host microRNAs (miRNAs) have been implicated in protection, but again we found that host cell miRNA expression was unaffected by the bacterium and neither do our findings suggest any involvement of the antiviral siRNA pathway. We conclude that Wolbachia may directly interfere with early events in virus replication such as translation of incoming viral RNA or RNA transcription, and this likely involves an intrinsic (as opposed to an induced) mechanism.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1005536</identifier><identifier>PMID: 27089431</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alphavirus ; Animals ; Aquatic insects ; Biology and Life Sciences ; Cell Line ; Drosophila melanogaster ; Drosophila melanogaster - genetics ; Genes ; Genetic aspects ; Genome, Viral - genetics ; Health aspects ; Humans ; Insects ; Medicine and Health Sciences ; MicroRNAs - genetics ; Mosquitoes ; Public health ; Research and Analysis Methods ; RNA, Small Interfering - genetics ; RNA, Viral - genetics ; Semliki Forest virus ; Symbiosis ; Togaviridae ; Transcription (Genetics) ; Transcription, Genetic ; Viral infections ; Virus replication ; Virus Replication - physiology ; Viruses ; Wolbachia ; Wolbachia - metabolism</subject><ispartof>PLoS pathogens, 2016-04, Vol.12 (4), p.e1005536-e1005536</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways. PLoS Pathog 12(4): e1005536. doi:10.1371/journal.ppat.1005536</rights><rights>2016 Rainey et al 2016 Rainey et al</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways. PLoS Pathog 12(4): e1005536. doi:10.1371/journal.ppat.1005536</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c694t-c3d83414fc44cdcf5e571a4510b7b412a33262958f8239161f45cc61122e31673</citedby><cites>FETCH-LOGICAL-c694t-c3d83414fc44cdcf5e571a4510b7b412a33262958f8239161f45cc61122e31673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1789548654/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1789548654?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27089431$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>McGraw, Elizabeth Ann</contributor><creatorcontrib>Rainey, Stephanie M</creatorcontrib><creatorcontrib>Martinez, Julien</creatorcontrib><creatorcontrib>McFarlane, Melanie</creatorcontrib><creatorcontrib>Juneja, Punita</creatorcontrib><creatorcontrib>Sarkies, Peter</creatorcontrib><creatorcontrib>Lulla, Aleksei</creatorcontrib><creatorcontrib>Schnettler, Esther</creatorcontrib><creatorcontrib>Varjak, Margus</creatorcontrib><creatorcontrib>Merits, Andres</creatorcontrib><creatorcontrib>Miska, Eric A</creatorcontrib><creatorcontrib>Jiggins, Francis M</creatorcontrib><creatorcontrib>Kohl, Alain</creatorcontrib><title>Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>The intracellular endosymbiotic bacterium Wolbachia can protect insects against viral infection, and is being introduced into mosquito populations in the wild to block the transmission of arboviruses that infect humans and are a major public health concern. To investigate the mechanisms underlying this antiviral protection, we have developed a new model system combining Wolbachia-infected Drosophila melanogaster cell culture with the model mosquito-borne Semliki Forest virus (SFV; Togaviridae, Alphavirus). Wolbachia provides strong antiviral protection rapidly after infection, suggesting that an early stage post-infection is being blocked. Wolbachia does appear to have major effects on events distinct from entry, assembly or exit as it inhibits the replication of an SFV replicon transfected into the cells. Furthermore, it causes a far greater reduction in the expression of proteins from the 3' open reading frame than the 5' non-structural protein open reading frame, indicating that it is blocking the replication of viral RNA. Further to this separation of the replicase proteins and viral RNA in transreplication assays shows that uncoupling of viral RNA and replicase proteins does not overcome Wolbachia's antiviral activity. This further suggests that replicative processes are disrupted, such as translation or replication, by Wolbachia infection. This may occur by Wolbachia mounting an active antiviral response, but the virus did not cause any transcriptional response by the bacterium, suggesting that this is not the case. Host microRNAs (miRNAs) have been implicated in protection, but again we found that host cell miRNA expression was unaffected by the bacterium and neither do our findings suggest any involvement of the antiviral siRNA pathway. We conclude that Wolbachia may directly interfere with early events in virus replication such as translation of incoming viral RNA or RNA transcription, and this likely involves an intrinsic (as opposed to an induced) mechanism.</description><subject>Alphavirus</subject><subject>Animals</subject><subject>Aquatic insects</subject><subject>Biology and Life Sciences</subject><subject>Cell Line</subject><subject>Drosophila melanogaster</subject><subject>Drosophila melanogaster - genetics</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genome, Viral - genetics</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Insects</subject><subject>Medicine and Health Sciences</subject><subject>MicroRNAs - genetics</subject><subject>Mosquitoes</subject><subject>Public health</subject><subject>Research and Analysis Methods</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Viral - genetics</subject><subject>Semliki Forest virus</subject><subject>Symbiosis</subject><subject>Togaviridae</subject><subject>Transcription (Genetics)</subject><subject>Transcription, Genetic</subject><subject>Viral infections</subject><subject>Virus replication</subject><subject>Virus Replication - 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To investigate the mechanisms underlying this antiviral protection, we have developed a new model system combining Wolbachia-infected Drosophila melanogaster cell culture with the model mosquito-borne Semliki Forest virus (SFV; Togaviridae, Alphavirus). Wolbachia provides strong antiviral protection rapidly after infection, suggesting that an early stage post-infection is being blocked. Wolbachia does appear to have major effects on events distinct from entry, assembly or exit as it inhibits the replication of an SFV replicon transfected into the cells. Furthermore, it causes a far greater reduction in the expression of proteins from the 3' open reading frame than the 5' non-structural protein open reading frame, indicating that it is blocking the replication of viral RNA. Further to this separation of the replicase proteins and viral RNA in transreplication assays shows that uncoupling of viral RNA and replicase proteins does not overcome Wolbachia's antiviral activity. This further suggests that replicative processes are disrupted, such as translation or replication, by Wolbachia infection. This may occur by Wolbachia mounting an active antiviral response, but the virus did not cause any transcriptional response by the bacterium, suggesting that this is not the case. Host microRNAs (miRNAs) have been implicated in protection, but again we found that host cell miRNA expression was unaffected by the bacterium and neither do our findings suggest any involvement of the antiviral siRNA pathway. We conclude that Wolbachia may directly interfere with early events in virus replication such as translation of incoming viral RNA or RNA transcription, and this likely involves an intrinsic (as opposed to an induced) mechanism.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27089431</pmid><doi>10.1371/journal.ppat.1005536</doi><oa>free_for_read</oa></addata></record> |
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subjects | Alphavirus Animals Aquatic insects Biology and Life Sciences Cell Line Drosophila melanogaster Drosophila melanogaster - genetics Genes Genetic aspects Genome, Viral - genetics Health aspects Humans Insects Medicine and Health Sciences MicroRNAs - genetics Mosquitoes Public health Research and Analysis Methods RNA, Small Interfering - genetics RNA, Viral - genetics Semliki Forest virus Symbiosis Togaviridae Transcription (Genetics) Transcription, Genetic Viral infections Virus replication Virus Replication - physiology Viruses Wolbachia Wolbachia - metabolism |
title | Wolbachia Blocks Viral Genome Replication Early in Infection without a Transcriptional Response by the Endosymbiont or Host Small RNA Pathways |
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