The Ebola virus: what we know, what we don’t know and why we don’t know. ?· The Ebola Virus: What…

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  • The Ebola virus: what we know, what we dont know and why we dont know.

    Aisha Belgore

  • The Ebola Virus: What we know, what we don't know and why we dont know.

    By Aisha Belgore

    Table of Contents ABSTRACT 2 ............................................................................................................................................................

    INTRODUCTION 2 ...................................................................................................................................................

    STUCTURE AND REPLICATION 4 .............................................................................................................................

    Nucleocapsid Proteins 5 .....................................................................................................................................

    Envelope Proteins 6 ............................................................................................................................................

    What we dont know about the proteins: The sGP Protein 7 .............................................................................

    Viral Protein Synthesis and ReplicaOon Within Cells 8 .......................................................................................

    TRANMISSION AND RESERVIOR HOSTS 10 .............................................................................................................

    Animal to Human Transmission 10 .....................................................................................................................

    Human to Human Transmission 11 ....................................................................................................................

    What we dont know about transmission: Droplet transmission 12 ..................................................................

    INFECTION AND PATHOGENESIS 15 ........................................................................................................................

    Receptor AWachment and Entry and Membrane Fusion Mechanisms 15 ..........................................................

    Immune System DeregulaOon 16 .......................................................................................................................

    Impairment of the vascular system 17 ............................................................................................................

    CoagulaOon 18 ...................................................................................................................................................

    Organ infecOon 19 ..............................................................................................................................................

    Death 20 .............................................................................................................................................................

    What InfecOon Routes do we not know 20 ........................................................................................................

    TREATMENT AND VACCINE 22 ................................................................................................................................

    Treatment Methods 22 .......................................................................................................................................

    Vaccine Developments 23 .................................................................................................................................

    CONCLUSION: WHY WE DONT KNOW? 24 ............................................................................................................

    Social Issues 25 ...................................................................................................................................................

    Geographic challenges 25 ..................................................................................................................................

    Economic and poliOcal Challenges 25 ................................................................................................................

    ScienOfic Challenges 25 ......................................................................................................................................

    BIBLIOGRAPHY 27...................................................................................................................................................

    1

  • ABSTRACT Ebola virus is a long filamentous virus which is the sister virus to Marburg virus and together they make up the Filovirdea family. There are 5 strains of Ebola virus: Sudan (SUDV), Reston (RESTV), Bundibugyo (BDBV), Tai forest (TAFV) and Ebola (EBOV- which was formally known Zaire Ebola). This report focuses on EBOV and the lethal Ebola Virus Disease (EVD) it causes in a human host. It also gives a detailed and in depth explanation of what is known about the virus i.e. the method used to infect its hosts, the function of its proteins, the mechanisms used to cause EVD in hosts and the effort being made by the scientific community to combat the disease. It is made evident in the report that a lot of the information available on Ebola is yet to be fully proven. Part of the purpose of writing the report are highlighting these grey areas and explain why further investigation is a challenge.

    INTRODUCTION Ebola viruses are the causative agents of Ebola Virus Disease in mammalian organisms. There are 5 species of the Ebola viruses. These are: Sudan (SUDV), Reston (RESTV), Bundibugyo (BDBV), Tai forest (TAFV) and Ebola (EBOV- which was formally known Zaire Ebola) . They all vary slightly in the sequence of their 1ribonucleic acid (RNA) and this causes them to all produce different versions of the same proteins. Because different proteins are produced they behave differently. For example, each strain of the virus can infect primates and cause the Ebola Virus Disease, however RESTV can only infect non-human primates . Of the 2 3four other strains which can infect humans, EBOV is the most lethal strain with a mortality rate varying in the range 25-90% . For this essay, EBOV will be the only strain considered. 4

    The Ebola Virus (EBOV), is a virus of order Mononegavirales, family Filovirdea, genus Ebolavirus and species Ebola . The Belgian virologist Peter Piot, who visited the area to carry out an epidemiological 5 6evaluation of the villages infected, named the genus after the closest river, the Ebola River; and the species after the country it was first discovered in, The Republic of Zaire (what is now Democratic Republic of Congo) . 7

    EBOV was first discovered in a small village called Yambuku. Its first known host was a primary school teacher who had previously been in contact with monkey and antelope meat. After a number of days he visited the hospital complaining to have symptoms identical to that of malaria which is a common illness in Zaire. The nurses at the hospital injected the malaria medicine Chloroquine into his bloodstream. As was common practice then, the needle used to administer his injection was later used for other patients that day. A fortnight later, he broke out with Ebola; his family, the people who attended his funeral and the people who also visited

    InternaOonal CommiWee on taxonomy of Viruses, 'Virus taxonomy: 2015 Release', Interna'onal Commi.ee on 1

    taxonomy of Viruses (ICTV), , [accessed 30 July, 2016].

    Richard Preston, THE HOT ZONE: THE CHLLING TRUE STORY OF AN EBOLA OUTBREAK (London: Transworld Publisher, 2

    1994), page 115.

    Jens Kunn, 'PROPOSAL FOR A REVISED TAXONOMYOF THE FILOVIRDEA: CLASSIFICATION, NAMES OF TAXA AND VIRUSES 3

    ANA VIRUS ABBREVIATIONS', Achieves of Virology, Vol.155, (December 2010), pp. 2083- 2103.

    Amanda Shaffer, 'Key Protein May Give Ebola Virus It is Opening', New York Times, 16 January 2012, pp.1-2.4

    InternaOonal CommiWee on taxonomy of Viruses, 'Virus taxonomy: 2015 Release', Interna'onal Commi.ee on 5

    taxonomy of Viruses (ICTV), , [accessed 30 July, 2016].

    Jens Kunn, 'PROPOSAL FOR A REVISED TAXONOMYOF THE FILOVIRDEA: CLASSIFICATION, NAMES OF TAXA AND VIRUSES 6

    ANA VIRUS ABBREVIATIONS', Achieves of Virology, Vol.155, (December 2010), pp. 2083- 2103.

    Carl Zimmer, 'A PLANET OF VIRUSES (Chicago and London: University of Chicago Press, 2015) pp.80.7

    2

  • the hospital the same day as him- two weeks earlier- all contracted the virus soon after. This led to the first known breakout of Ebola in 1976 . 8 9 10

    EBOV is also responsible for most recent outbreak in 2014 in West Africa which concluded on the January 14th 2016 with its final casualty in Liberia. Liberia was declared Ebola free by the Centre for Disease Control (CDC) and the World health Organisation (WHO) after going 42 days without a reported case which is double the maximum incubation time of the virus (21 days) . The 2014 outbreak originated from Meliandou, a small 11Guinea village. This was the first time this region of Africa was infected with the virus . During the outbreak 12EBOV infected 28,652 people globally (as of April 4th 2016), of this 28616 were in Sierra Leone, Liberia and Guinea which were the most affected countries. Other countries such as The United States of America, Nigeria, United Kingdom, Spain, Italy, Mali and Senegal had fewer casualties totalling to 36 cases in total . 13Sierra Leone, Guinea and Liberia- the heavily infected countries received help from global institutions and charities such as World Health Organisation and Red Cross . 14 15

    Throughout the rest of this report each section will include a descriptive subsection, explaining what we do know about the virus then a subsequent subsection describing what is unknown about that virus in the context of the essay. In the conclusion section of the report, the why we dont know is fully explained.

    Richard Preston, THE HOT ZONE: THE CHLLING TRUE STORY OF AN EBOLA OUTBREAK (London: Transworld Publisher, 8

    1994), page 115.

    InternaOonal CommiWee on taxonomy of Viruses, 'Virus taxonomy: 2015 Release', Interna'onal Commi.ee on 9

    taxonomy of Viruses (ICTV), , [accessed 30 July, 2016].

    Jens Kunn, 'PROPOSAL FOR A REVISED TAXONOMYOF THE FILOVIRDEA: CLASSIFICATION, NAMES OF TAXA AND 10

    VIRUSES ANA VIRUS ABBREVIATIONS', Achieves of Virology, Vol.155, (December 2010), pp. 2083- 2103.

    Unknown Author, '2014 Ebola Outbreak in West Africa- Case Counts', Centres for disease control and preven'on, 11

    , [accessed 29 July, 2016].

    World Health OrganisaOon, 'Latest Ebola Outbreak Over in Liberia; West Africa is at zero, but new flare ups likely to 12

    occur,' World Health OrganisaOon, , [accessed 02 August, 2016].

    Unknown Author, '2014 Ebola Outbreak in West Africa- Case Counts', Centres for disease control and preven'on, 13

    , [accessed 29 July, 2016].

    American Red Cross, Ebola Outbreak In Africa, American Red Cross hWp://www.redcross.org/about-us/our-work/14

    internaOonal-services/ebola#Overview [accessed 04 November, 2016].

    The World Bank, World Bank Ebola Response Fact Sheet, The World Bank hWp://www.worldbank.org/en/topic/15

    health/brief/world-bank-group-ebola-fact-sheet [Accessed 04 November 16].

    3

    http://www.worldbank.org/en/topic/health/brief/world-bank-group-ebola-fact-sheethttp://www.redcross.org/about-us/our-work/international-services/ebola#Overview

  • 16

    STUCTURE AND REPLICATION EBOV is a member of the family Filovirus and the Latin derivative of filovirus are the words 'filum and 'virdea' these translates to 'thread' and 'virus' . Hence, Ebola has a long and tubular structure. The length of 17individual virions vary in the range of 860 - 1200 nm (10-9 m) long which is significantly larger than the average virus size, this is another feature common to filoviruses, they're larger than other virus families. However, the width of virions is fixed as all are 80 nm wide. It is described as having a "6 shape" or "U- shape" due to the bending and looping in the viruses structure as seen in Figure 1 . 18 19 20

    The EBOV contains a single-stranded nonsegmented negative sense (running from 3 to 5) ribonucleic Acid (SS-RNA) genome. This Genome comprises 7 genes arranged on one long linear strand, coding for 8 proteins and is 18957 bases long. This makes up for approximately 1% of an individual virions mass. The seven genes are: NP, VP35, VP40, GP, VP30, VP24 and L. As shown in figure 2 the genome is capped with leader and trainer regions of nucleotides. In these regions, there are origins for replication and promoters for transcription initiation, and encapsidation signals. Also, shown in figure 2 by the purple arrows there are overlaps between VP35 and VP40, GP and VP30 and the last overlap between VP24 and L. These overlaps mean that during

    Jeffrey DelVisco, A Witness to Ebolas Discovery The New York Times, 9 August 2014.16

    DicOonary.com, 'Filovirus', Dictonary.com, hWps://dicOonary.com/browse/filovirus 17

    Heinz Feldmann, Anthony Sanchez, and Thomas W. Geizsbert, FILOVIRDEA: MARBURG AND EBOLA VIRUS, FEILD 18

    VIROLOGY, edited by David Knipe and Peter M. Howly (Philadelphia: LipcoW Williams & Wilkins, 2013), pp. 923 945.

    Centre for Biosecurity, 'Ebolavirus', Public Health Agency of Canada, , [03 November, 2016].

    Elke Muhlberger, GENOME ORGANISATION, REPLICATION, AND TRANSCRIPTION, EBOLA AND MARBURG VIRUSES: 20

    MOLECULAR AND CELLULAR BIOLOGY, edited by Hanz- Dieter Klenk and Heinz Feldmann (Trowbridge: The Cromwell Press, 2004) pp. 1-26

    4

    Figure 1: A transition electron microscope (TEM) micrograph of the Ebola Virus. Taken by Fredrick A. Murphy for Centre for Disease Control.

    https://dictionary.com/browse/filovirus

  • transcription combinations of genes are transcribed by RNA polymerase into an mRNA however the different proteins have their start codon positioned at different locations along the mRNA . 21 22 23

    !

    Each gene produces a corresponding protein, except for the GP gene which also produces both the GP and sGP proteins . The proteins are categorized into two groups, those that contribute to the envelope structure 24and those involved in formation of the nucleocapsid . 25

    Nucleocapsid Proteins The four proteins NP, VP35, VP30 and L are all nucleocapsid associated proteins. NP and VP30 are the major and minor nucleocapsid proteins. NP binds to the RNA forming NP-RNA this process is called encapsidation. When combined, the two macromolecules form coil complex of 40nm diameters. During virion replication, the NP protein must be present to encapsidate the new viral RNA produced as a result of transcription 11. VP30 has two roles, one is being included to NP, effectively joining the nucleocapsid; the other is as a transcription activator, promoting the attachment of the polymerase protein to the viral genome to produce mRNA. The rate at which the protein performs its roles is based on the amount of phosphorylation it has undergone. When highly phosphorylated it will fully bind to NP however it will not act efficiently as an activator. On the other hand, w...