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==Ebola Virus RNA-Dependent RNA Polymerase==
==Ebola Virus RNA-Dependent RNA Polymerase==
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<StructureSection load='EbolaRDRPModel.pdb' size='340' side='right' caption='Ebola Virus RNA-Dependent RNA Polymerase' scene=''>
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<scene name='89/891377/Ebov_rdrp/1'>Ebola Virus RNA-Dependent RNA Polymerase</scene>
==Disease==
==Disease==

Revision as of 09:56, 12 October 2021

Contents

Ebola Virus RNA-Dependent RNA Polymerase

Disease

Ebola virus (EBOV) causes Ebola virus disease (EVD), a fatal hemorrhagic disease discovered in 1976.[1] Sources of infection are mainly linked with “hunting wildlife, exposure to animal carcasses found in the forest, or contact with the putative virus reservoir, bats”.[2]

EVD pathogenesis in humans consists of three phases with symptoms normally occurring after an incubation period of 2-21 days.[3] In the first phase, symptoms during the first few days include nonspecific fever, headache, and myalgia.[4] This is followed by a “gastrointestinal phase” characterized by symptoms including diarrhea, vomiting, abdominal discomfort, and dehydration.[5] The final and advanced phase of the illness consist of kidney and liver function failure, often resulting in “metabolic compromise, convulsion, shock, and death due to mucosal bleeding, bloody diarrhea, and multi-organ failure within 16 days after the first symptoms appear”.[6]

Since EBOV's discovery, there have been 20 known outbreaks restricted primarily to African countries with minor spread to neighboring countries.[7] The most recent outbreak of Ebola occurred during a three-month span in the Democratic Republic of the Congo this year, the country’s 4th in the past three years.[1] Since its start in February, there was a total of eleven confirmed cases with six recoveries and six deaths and one probable case emanating from four health zones in North Kivu.[2] There is also an ongoing outbreak in Guinea, West Africa which started in the same month as the outbreak in the DRC.[3]

There is currently no vaccine for EVD, but there are currently eight vaccine candidates in human clinical trials that all target the Ebola virus glycoprotein (GP), one of the nine known proteins to be expressed by the virus’s genome.[8] However, these vaccines are different from each other in the immune responses they elicit, the antigen delivery system, and their respective side-effect profiles.[9]

RNA Classification

Ebola is part of the Filoviridae family of single-stranded negative-sense RNA viruses of approximately 19 kb.[10] The 19 kb RNA encodes for “glycoproteins (i.e., GP, sGP, ssGP), nucleoproteins, virion proteins (i.e., VP 24, 30, 40) and the RNA-dependent RNA polymerase”.[11] In EBOV, the RNA dependent RNA polymerase in conjunction with NP, VP30, and VP35 form the RNP complex in viral genome transcription and replication.[12] RDRP binds to the 3’ leader promoter and changes EBOV’s negative-sense RNA into positive-sense messenger RNA to produce Ebola proteins that produce new viral particles (virions).[13]

Function of RNA-Dependent RNA Polymerase

RNA-dependent RNA polymerases (RdRp) are critical to the replication and transcription of RNA viruses.[14] Due to this protein's importance in the viral life cycle, they are feasible targets for vaccine development.[15] Inhibition of RdRp results in the inhibition of transcription of the viral genome, ultimately resulting in no new production of virions for the virus.

Structural Features of Ebola Virus RNA-Dependent RNA Polymerase[4]

EBOV has a monomeric RNA-dependent RNA polymerase and as such, shares the characteristic of other monomeric RdRp composed of the fingertips, palm, and thumb subdomains. [16] The 3D structure described here was produced by running one Zaire Ebola virus L protein sequence (Sierra Leona, Makona-G3686.1; AIE11922) on the homology modeling program, SwissModel. [5] The is composed of residues 417-439 and 489-563, the is composed of residues 440-488 and 563-666, and the is made up of residues 667-704.[17] The highly conserved motifs A-E were identified in the palm subdomain of the EBOV RdRp, but motifs F and G, which are not part of the active site, were not identified.[18]

RNA Transcription and Translation

</StructureSection>

References

  1. ↑ Furuyama W, Marzi A. Ebola Virus: Pathogenesis and Countermeasure Development. Annu Rev Virol. 2019 Sep 29;6(1):435-458. doi:, 10.1146/annurev-virology-092818-015708. PMID:31567063 doi:http://dx.doi.org/10.1146/annurev-virology-092818-015708
  2. ↑ Furuyama W, Marzi A. Ebola Virus: Pathogenesis and Countermeasure Development. Annu Rev Virol. 2019 Sep 29;6(1):435-458. doi:, 10.1146/annurev-virology-092818-015708. PMID:31567063 doi:http://dx.doi.org/10.1146/annurev-virology-092818-015708
  3. ↑ Furuyama W, Marzi A. Ebola Virus: Pathogenesis and Countermeasure Development. Annu Rev Virol. 2019 Sep 29;6(1):435-458. doi:, 10.1146/annurev-virology-092818-015708. PMID:31567063 doi:http://dx.doi.org/10.1146/annurev-virology-092818-015708
  4. ↑ Furuyama W, Marzi A. Ebola Virus: Pathogenesis and Countermeasure Development. Annu Rev Virol. 2019 Sep 29;6(1):435-458. doi:, 10.1146/annurev-virology-092818-015708. PMID:31567063 doi:http://dx.doi.org/10.1146/annurev-virology-092818-015708
  5. ↑ Furuyama W, Marzi A. Ebola Virus: Pathogenesis and Countermeasure Development. Annu Rev Virol. 2019 Sep 29;6(1):435-458. doi:, 10.1146/annurev-virology-092818-015708. PMID:31567063 doi:http://dx.doi.org/10.1146/annurev-virology-092818-015708
  6. ↑ Furuyama W, Marzi A. Ebola Virus: Pathogenesis and Countermeasure Development. Annu Rev Virol. 2019 Sep 29;6(1):435-458. doi:, 10.1146/annurev-virology-092818-015708. PMID:31567063 doi:http://dx.doi.org/10.1146/annurev-virology-092818-015708
  7. ↑ Malvy D, McElroy AK, de Clerck H, Gunther S, van Griensven J. Ebola virus disease. Lancet. 2019 Mar 2;393(10174):936-948. doi: 10.1016/S0140-6736(18)33132-5. Epub, 2019 Feb 15. PMID:30777297 doi:http://dx.doi.org/10.1016/S0140-6736(18)33132-5
  8. ↑ Furuyama W, Marzi A. Ebola Virus: Pathogenesis and Countermeasure Development. Annu Rev Virol. 2019 Sep 29;6(1):435-458. doi:, 10.1146/annurev-virology-092818-015708. PMID:31567063 doi:http://dx.doi.org/10.1146/annurev-virology-092818-015708
  9. ↑ Furuyama W, Marzi A. Ebola Virus: Pathogenesis and Countermeasure Development. Annu Rev Virol. 2019 Sep 29;6(1):435-458. doi:, 10.1146/annurev-virology-092818-015708. PMID:31567063 doi:http://dx.doi.org/10.1146/annurev-virology-092818-015708
  10. ↑ Furuyama W, Marzi A. Ebola Virus: Pathogenesis and Countermeasure Development. Annu Rev Virol. 2019 Sep 29;6(1):435-458. doi:, 10.1146/annurev-virology-092818-015708. PMID:31567063 doi:http://dx.doi.org/10.1146/annurev-virology-092818-015708
  11. ↑ Rojas M, Monsalve DM, Pacheco Y, Acosta-Ampudia Y, Ramirez-Santana C, Ansari AA, Gershwin ME, Anaya JM. Ebola virus disease: An emerging and re-emerging viral threat. J Autoimmun. 2020 Jan;106:102375. doi: 10.1016/j.jaut.2019.102375. Epub 2019 Dec , 3. PMID:31806422 doi:http://dx.doi.org/10.1016/j.jaut.2019.102375
  12. ↑ Rojas M, Monsalve DM, Pacheco Y, Acosta-Ampudia Y, Ramirez-Santana C, Ansari AA, Gershwin ME, Anaya JM. Ebola virus disease: An emerging and re-emerging viral threat. J Autoimmun. 2020 Jan;106:102375. doi: 10.1016/j.jaut.2019.102375. Epub 2019 Dec , 3. PMID:31806422 doi:http://dx.doi.org/10.1016/j.jaut.2019.102375
  13. ↑ Rojas M, Monsalve DM, Pacheco Y, Acosta-Ampudia Y, Ramirez-Santana C, Ansari AA, Gershwin ME, Anaya JM. Ebola virus disease: An emerging and re-emerging viral threat. J Autoimmun. 2020 Jan;106:102375. doi: 10.1016/j.jaut.2019.102375. Epub 2019 Dec , 3. PMID:31806422 doi:http://dx.doi.org/10.1016/j.jaut.2019.102375
  14. ↑ Tchesnokov EP, Raeisimakiani P, Ngure M, Marchant D, Gotte M. Recombinant RNA-Dependent RNA Polymerase Complex of Ebola Virus. Sci Rep. 2018 Mar 5;8(1):3970. doi: 10.1038/s41598-018-22328-3. PMID:29507309 doi:http://dx.doi.org/10.1038/s41598-018-22328-3
  15. ↑ Tchesnokov EP, Raeisimakiani P, Ngure M, Marchant D, Gotte M. Recombinant RNA-Dependent RNA Polymerase Complex of Ebola Virus. Sci Rep. 2018 Mar 5;8(1):3970. doi: 10.1038/s41598-018-22328-3. PMID:29507309 doi:http://dx.doi.org/10.1038/s41598-018-22328-3
  16. ↑ Jacome R, Becerra A, Ponce de Leon S, Lazcano A. Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic Implications. PLoS One. 2015 Sep 23;10(9):e0139001. doi: 10.1371/journal.pone.0139001., eCollection 2015. PMID:26397100 doi:http://dx.doi.org/10.1371/journal.pone.0139001
  17. ↑ Jacome R, Becerra A, Ponce de Leon S, Lazcano A. Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic Implications. PLoS One. 2015 Sep 23;10(9):e0139001. doi: 10.1371/journal.pone.0139001., eCollection 2015. PMID:26397100 doi:http://dx.doi.org/10.1371/journal.pone.0139001
  18. ↑ Jacome R, Becerra A, Ponce de Leon S, Lazcano A. Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic Implications. PLoS One. 2015 Sep 23;10(9):e0139001. doi: 10.1371/journal.pone.0139001., eCollection 2015. PMID:26397100 doi:http://dx.doi.org/10.1371/journal.pone.0139001
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