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Etiology of Ebola and Existing Treatment

PHM142 Fall 2019 Instructor : Chesa Dojo Soeandy Coordinator: Jeffrey Henderson. Etiology of Ebola and Existing Treatment. Annie Yung Ching Shi, Michelle (Eun Sun) Choi, Yuehan (Carina ) Zhao, and Eulaine Ma October 1st, 2019. What causes Ebola Virus Disease?.

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Etiology of Ebola and Existing Treatment

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  1. PHM142 Fall 2019 Instructor: Chesa Dojo Soeandy Coordinator: Jeffrey Henderson Etiology of Ebola and Existing Treatment Annie Yung Ching Shi, Michelle (Eun Sun) Choi, Yuehan (Carina) Zhao, and Eulaine Ma October 1st, 2019

  2. What causes Ebola Virus Disease? • 4 different viruses: Bundibugyo virus (BDBV), Sudan virus (SUDV), Tai Forest virus (TAFV) and Zaire ebola virus (EBOV) • EBOV is responsible for most outbreaks and most dangerous https://en.wikipedia.org/wiki/Zaire_ebolavirus

  3. EBOV (Zaire ebola virus) • Single stranded RNA (19000 nucleotides long) • On this RNA there are 7 genes for 7 proteins: • Nucleoprotein (NP) • Polymerase cofactor • VP35 • GP • Transcription Activator (VP30) • VP24 • RNA polymerase (L) http://jonlieffmd.com/blog/the-very-intelligent-ebola-virus-takes-front-and-center

  4. History of Ebola https://upload.wikimedia.org/wikipedia/commons/2/29/Ebola_Outbreak_Map_%28ongoing%29.png

  5. History of Ebola • Initial appearance: 1976 in Sudan and Democratic Republic of Congo • 2014-2016 outbreak in Sierra Leone, Liberia and Guinea was largest outbreak https://www.cdc.gov/vhf/ebola/history/distribution-map.html

  6. Transmission • From animals: • Fruit bats are natural reservoirs of Ebola • Transmitted to humans through bodily fluids of infected animals • Between person to person • Bodily fluids or blood from people who are infected • Objects that have been contaminated (vomit, feces) • Burial ceremony of the diseased • Healthcare workers https://www.batworlds.com/fruit-bat/

  7. Symptoms • Clinical Outcome • Ebola hemorrhagic fever • Disseminated intravascular coagulation (DIC) • Shock • Death • Incubation period of 2 to 21 days • Initial symptoms • Fever, fatigue, muscle pains • Headaches • Sore throats • Later symptoms: • Vomiting, diarrhea • Impaired organ functions • Internal and external bleeding

  8. The fatality rate for ebola virus disease is 25-90%. A lot of unknowns: We do not know why some people survive

  9. Virology Viral Cycle • Entry • Replication • Release https://www.researchgate.net/profile/Sara_Richter2/publication/325705470/figure/fig4/AS:642830506655744@1530274144101/Schematic-representation-of-the-viral-life-cycle-The-virus-recognizes-and-binds-the-host.png

  10. Virology (entry of the virus) Glycoproteins on the Ebola virus bind to receptors on human cells C-type lectins (DC-SIGN) Macrophages & dendritic cells Integrin-like receptors Binding triggers macropinocytosis https://scx1.b-cdn.net/csz/news/800/2018/4-newresearchp.jpg

  11. Virology (inside the host cell) Transported to endosomes & lysosomes GP cleaved into GP2 Fusion between viral & endosomal membranes Release of nucleocapsid RNA polymerase uncoats the nucleocapsid https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495366/bin/cdd201567f2.jpg

  12. Virology (inside the host cell) https://d2vlcm61l7u1fs.cloudfront.net/media%2F6f6%2F6f672503-f8aa-4e76-a0eb-a837d3ace7b4%2FphpdZUF14.png

  13. Virology (leaving the host cell) Progeny virions accumulate near the cell membrane Bud off from the cell Infect other cells & repeat the cycle https://microbewiki.kenyon.edu/images/thumb/5/5c/Ebola_Budding.jpg/400px-Ebola_Budding.jpg

  14. Ebola Virus Disease (EVD) Pathogenesis Infection Immune dysregulation Clinical Outcome • Ebola Hemorrhagic Fever • Disseminated Intravascular Coagulation • Shock • Death

  15. EVD Pathogenesis: Immune dysregulation • Interferons (IFNs) are the first line of defense against viral infection Inhibition of viral replication MHC class I molecules Proinflammatory cytokines IFN Un-infected cell Infected cell

  16. EVD Pathogenesis: Immune dysregulation • EBOV evades the immune system through viral proteins VP24, VP30, VP35 • VP35 inhibits IFN production • VP24 disrupts IFN signalling Inhibition of viral replication MHC class I molecules Proinflammatory cytokines IFN Un-infected cell Infected cell

  17. https://www.sciencedirect.com/science/article/pii/S1357272505000725https://www.sciencedirect.com/science/article/pii/S1357272505000725

  18. https://www.sciencedirect.com/science/article/pii/S1357272505000725https://www.sciencedirect.com/science/article/pii/S1357272505000725

  19. Viral replication leads to necrosis of infected cells • Less immune cells to fight infection • Tissue injury and organ failure https://www.sciencedirect.com/science/article/pii/S1357272505000725

  20. Infected cells release proinflammatory cytokines, chemokines, nitric oxide • Recruitment of more immune cells • More cytokines → cytokine storm • Systemic blood vessel permeability → shock • More infection of target cells https://www.sciencedirect.com/science/article/pii/S1357272505000725

  21. Overexpression of tissue factor (TF) in infected macrophages • Overactivation of extrinsic pathway • Leads to disseminated intravascular coagulation (DIC) https://www.sciencedirect.com/science/article/pii/S1357272505000725

  22. IFN Clinical Outcome Ebola Hemorrhagic Fever Disseminated Intravascular Coagulation Shock Death https://www.sciencedirect.com/science/article/pii/S1357272505000725

  23. Current Treatments for Ebola • Basic supportive care: • IV fluids and electrolytes • Oxygen therapy • Stabilizing blood pressure with medication • Managing vomiting, diarrhea, fever, pain • Treating other infections as they occur • Currently, no FDA-approved antiviral drugs • But...

  24. 2018 PALM Study • Following 2018 East DRC Outbreak, PALM launched to study 4 investigational treatments: • ZMapp, remdesivir, mAb114, REGN-EB3 • mAb114 and REGN-EB3 showed most promising results in preliminary report; are in active use https://www.nih.gov/news-events/news-releases/independent-monitoring-board-recommends-early-termination-ebola-therapeutics-trial-drc-because-favorable-results-two-four-candidates

  25. mAb114 • mAb114 is a human IgG1 antibody that targets the receptor-binding domain of EBOV glycoprotein • Isolated from survivor of 1995 Kikwit outbreak • Neutralizing effect: prevents interaction of EBOV glycoprotein with NPC1 receptor on human cells • Impedes virus from entering & infecting target cell https://www.nature.com/articles/s41590-018-0233-9

  26. REGN-EB3 • Co-formulated cocktail composed of 3 human monoclonal antibodies that target 3 non-overlapping epitopes on EBOV and can bind simultaneously • Goal is to reduce generation & selection of resistant virus strains during treatment https://www.nature.com/articles/s41590-018-0233-9

  27. Summary • Of 4 Ebola viruses, EBOV is responsible for most outbreaks and most dangerous • Transmitted through bodily fluids, blood, contaminated objects • Glycoproteins on the virus surface bind to receptors on host cells, then it’s engulfed by macropinocytosis • The virus then transcribes, translates, and replicates using the host cell’s machinery • Progeny virus exits cell by budding off the host cell, gaining their envelopes from cell membrane • Ebola virus disease results from infection of monocytes, macrophages and dendritic cells and subsequent immune dysregulation • EBOV genome contains viral proteins that inhibit production and signalling of antiviral cytokine IFN • Leads to organ failure, cytokine storm, shock, and disseminated intravascular coagulation (small blood clots throughout bloodstream) • 2 promising Ebola drugs: mAb114 and REGN-EB3 • mAb114 - single monoclonal antibody (mAb); targets receptor-binding domain of EBOV • REGN-EB3 - co-formulated cocktail of 3 mAbs; target 3 different epitopes on EBOV

  28. References “2014-2016 Ebola Outbreak in West Africa | History | Ebola (Ebola Virus Disease) | CDC.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, www.cdc.gov/vhf/ebola/history/2014-2016-outbreak/index.html. Bray, Mike, and Thomas W. Geisbert. “Ebola Virus: The Role of Macrophages and Dendritic Cells in the Pathogenesis of Ebola Hemorrhagic Fever.” The International Journal of Biochemistry & Cell Biology, vol. 37, no. 8, 2005, pp. 1560–1566., doi:10.1016/j.biocel.2005.02.018. “Ebola Virus Disease.” World Health Organization, World Health Organization, www.who.int/news-room/fact-sheets/detail/ebola-virus-disease. “Ebola Virus Disease.” Wikipedia, Wikimedia Foundation, 19 Sept. 2019, en.wikipedia.org/wiki/Ebola_virus_disease#Virology. Falasca, L, et al. “Molecular Mechanisms of Ebola Virus Pathogenesis: Focus on Cell Death.” Cell Death and Differentiation, Nature Publishing Group, Aug. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4495366/. Falasca, L, et al. “Molecular Mechanisms of Ebola Virus Pathogenesis: Focus on Cell Death.” Cell Death and Differentiation, Nature Publishing Group, Aug. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4495366/. Gaudinski, Martin R, et al. “Safety, Tolerability, Pharmacokinetics, and Immunogenicity of the Therapeutic Monoclonal Antibody mAb114 Targeting Ebola Virus Glycoprotein (VRC 608): an Open-Label Phase 1 Study.” The Lancet, vol. 393, no. 10174, 2019, pp. 889–898., doi:10.1016/s0140-6736(19)30036-4. “Independent Monitoring Board Recommends Early Termination of Ebola Therapeutics Trial in DRC Because of Favorable Results with Two of Four Candidates.” National Institutes of Health, U.S. Department of Health and Human Services, 12 Aug. 2019, www.nih.gov/news-events/news-releases/independent-monitoring-board-recommends-early-termination-ebola-therapeutics-trial-drc-because-favorable-results-two-four-candidates. “Infection Mechanism of Genus Ebolavirus.” Microbewiki, microbewiki.kenyon.edu/index.php/Infection_Mechanism_of_Genus_Ebolavirus#Viral_Entry. Misasi, John, and Nancy J. Sullivan. “Camouflage and Misdirection: The Full-On Assault of Ebola Virus Disease.” Cell, vol. 159, no. 3, 2014, pp. 477–486., doi:10.1016/j.cell.2014.10.006. Murphy, Kenneth, et al. Janeway's Immunobiology. Garland Science, Taylor & Francis Group, 2017. “Signs and Symptoms | Ebola Hemorrhagic Fever | CDC.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, www.cdc.gov/vhf/ebola/symptoms/index.html. Sivapalasingam, Sumathi, et al. “Safety, Pharmacokinetics, and Immunogenicity of a Co-Formulated Cocktail of Three Human Monoclonal Antibodies Targeting Ebola Virus Glycoprotein in Healthy Adults: a Randomised, First-in-Human Phase 1 Study.” The Lancet Infectious Diseases, vol. 18, no. 8, 2018, pp. 884–893., doi:10.1016/s1473-3099(18)30397-9. Sophie Novack, National Journal. “What Is the Ebola Virus's Survival Rate? And Other Key Questions About the Epidemic.” The Atlantic, Atlantic Media Company, 30 Sept. 2014, www.theatlantic.com/politics/archive/2014/09/what-is-the-ebola-viruss-survival-rate-and-other-key-questions-about-the-epidemic/440442/. “Treatment | Ebola (Ebola Virus Disease) | CDC.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, www.cdc.gov/vhf/ebola/treatment/index.html.

  29. Supplementary Slides

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