Ebola virus

Ebola virus (EBOV, formerly designated Zaire ebolavirus) is the sole member of the Zaire ebolavirus species, and the most dangerous of the five known viruses within the genus Ebolavirus. Four of the five known ebolaviruses cause a severe and often fatal hemorrhagic feverin humans and other mammals, known as Ebola virus disease. The virus and its species were both originally named for Zaire (now the Democratic Republic of Congo), the country where it was first described, and was at first suspected to be a new "strain" of the closely related Marburg virus; the virus (but not its species) was renamed to "Ebola virus" in 2010 to avoid confusion. The species is avirological taxon species included in the genus Ebolavirus, family Filoviridae (whose members are called Filovirus), orderMononegavirales. The Zaire ebolavirus species is also the type species (reference or example species) for ebolavirus. Its natural reservoir is believed to be bats, particularly fruit bats, and it is primarily transmitted between humans and from animals to humans, through body fluids.

The EBOV genome is approximately 19,000 base pairs long. It encodes seven structural proteins: nucleoprotein (NP), polymerase cofactor(VP35), (VP40), GP, transcription activator (VP30), VP24, and RNA polymerase (L). Its is difficult to study due to the virulent nature of the virus.

Because of its high mortality rate, EBOV is also listed a select agent, World Health Organization Risk Group 4 Pathogen (requiring Biosafety Level 4-equivalent containment), a U.S. National Institutes of Health/National Institute of Allergy and Infectious Diseases Category A Priority Pathogen, U.S. CDC Centers for Disease Control and Prevention Category A Bioterrorism Agent, and listed as a Biological Agent for Export Control by the Australia Group.

Structure

Phylogenetic tree comparing the Ebolavirus and Marburgvirus. Numbers indicate percent confidence of branches.

EBOV carries a negative-sense RNA genome in virions that are cylindrical/tubular, and contain viral envelope, matrix, and nucleocapsid components. The overall cylinders are generally approx. 80 nm in diameter, and having a virally encoded glycoprotein (GP) projecting as 7-10 nm long spikes from its lipid bilayer surface. The cylinders are of variable length, typically 800 nm, but sometimes up to 1000 nm long. The outer viral envelope of the virion is derived by budding from domains of host cell membrane into which the GP spikes have been inserted during their biosynthesis. Individual GP molecules appear with spacings of about 10 nm. Viral proteins VP40and VP24 are located between the envelope and the nucleocapsid (see following), in the matrix space.[7] At the center of the virion structure is the nucleocapsid, which is composed of a series of viral proteins attached to a 18–19 kb linear, negative-sense RNA without 3′-polyadenylation or 5′-capping (see following); the RNA is helically wound and complexed with the NP, VP35, VP30, and L proteins; this helix has a diameter of 80 nm and contains a central channel of 20–30 nm in diameter.

The overall shape of the virions after purification and visualization (e.g., by ultracentrifugation and electron microscopy, respectively) varies considerably; simple cylinders are far less prevalent than structures showing reversed direction, branches, and loops (i.e., U-, shepherd's crook-, 9- or eye bolt-shapes, or other or circular/coiled appearances), the origin of which may be in the laboratory techniques applied.The characteristic "threadlike" structure is, however, a more general morphologic characteristic of filoviruses (alongside their GP-decorated viral envelope, RNA nucleocapsid, etc.).

Entry

There are two candidates for host cell entry proteins. The first is the host-encoded Niemann–Pick C1 (NPC1), a cholesterol transporter protein, appears to be essential for entry of Ebola virions into the host cell, and for its ultimate replication. In one study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse-adapted Ebola virus. In another study, small molecules were shown to inhibit Ebola virus infection by preventing viral envelope glycoprotein (GP) from binding to NPC1. Hence, NPC1 was shown to be critical to entry of this filovirus, because it mediates infection by binding directly to viral GP.

When cells from Niemann Pick Type C patients lacking this transporter were exposed to Ebola virus in the laboratory, the cells survived and appeared impervious to the virus, further indicating that Ebola relies on NPC1 to enter cells; mutations in the NPC1 gene in humans were conjectured as a possible mode to make some individuals resistant to this deadly viral disease. The same studies described similar results regarding NPC1's role in virus entry for Marburg virus, a relatedfilovirus. A further study has also presented evidence that NPC1 is critical receptor mediating Ebola infection via its direct binding to the viral GP, and that it is the second "lysosomal" domain of NPC1 that mediates this binding.

The second candidate is TIM-1 (aka HAVCR1). TIM-1 was shown to bind to the receptor binding domain of the EBOV glycoprotein, to increase the receptivity of Vero cells. Silencing its effect with siRNA prevented infection of Vero cells. TIM1 is expressed in tissues known to be seriously impacted by EBOV lysis (trachea, cornea, and conjunctiva). A monoclonal antibody against the IgV domain of TIM-1, ARD5, blocked EBOV binding and infection.

Together, these studies suggest NPC1 and TIM-1 may be potential therapeutic targets for an Ebola anti-viral drug and as a basis for a rapid field diagnostic assay.

Replication

Being acellular, viruses such as Ebola do not replicate through any type of cell division; rather, they use a combination of host- and virally encoded enzymes, alongside host cell structures, to produce multiple copies of themselves; these then self-assemble into viral macromolecular structures in the host cell. The virus completes a set of steps when infecting each individual cell:

The virus begins its attack by attaching to host receptors through the glycoprotein (GP) surface peplomer and is endocytosed into macropinosomes in the host cell. To penetrate the cell, the viral membrane fuses with vesicle membrane, and the nucleocapsid is released into the cytoplasm. Encapsidated, negative-sense genomic ssRNA is used as a template for the synthesis (3'-5') of polyadenylated, monocistronic mRNAs and, using the host cell's ribosomes, tRNA molecules, etc., the mRNA is translated into individual viral proteins.

These viral proteins are processed, a glycoprotein precursor (GP0) is cleaved to GP1 and GP2, which are then heavily glycosylated using cellular enzymes and substrates. These two molecules assemble, first into heterodimers, and then into trimers to give the surface peplomers. Secreted glycoprotein (sGP) precursor is cleaved to sGP and delta peptide, both of which are released from the cell. As viral protein levels rise, a switch occurs from translation to replication. Using the negative-sense genomic RNA as a template, a complementary +ssRNA is synthesized; this is then used as a template for the synthesis of new genomic (-)ssRNA, which is rapidly encapsidated.

The newly formed nucleocapsids and envelope proteins associate at the host cell's plasma membrane; budding occurs, destroying the cell.

Ecology

Ebolavirus is a zoonotic pathogen. Intermediary hosts have been reported to be "various species of fruit bats ... throughout central and sub-Saharan Africa", but infection in bats has not been proven yet. End hosts are humans and great apes, infected through bat contact or through other end hosts. Pigs on the Philippine islands have been reported to be infected with Restonvirus, so other interim or amplifying hosts may exist.

Ebola virus disease

Ebola virus is one of the four ebolaviruses known to cause disease in humans. It has the highest case-fatality rate of these ebolaviruses, averaging 83% since first described in 1976, although fatality rates up to 90% have been recorded in one epidemic (2002–03). There have also been more outbreaks of ebola virus than of any other ebolavirus. The first outbreak occurred on 26 August 1976 in Yambuku. The first recorded case was Mabalo Lokela, a 44‑year-old schoolteacher. The symptoms resembled malaria, and subsequent patients received quinine. Transmission has been attributed to reuse of unsterilized needles and close personal contact, body fluids and places where the person has touched.

Species inclusion criteria

To be considered a member of the species Zaire ebolavirus, a virus of the genus Ebolavirus is required to fulfill certain requirements:

·         it is found in the Democratic Republic of the Congo, Gabon, or the Republic of the Congo

·         it has a genome with two or three gene overlaps (VP35/VP40, GP/VP30, VP24/L)

·         it has a genomic sequence that differs from the type virus by less than 30%

Furthermore, the virus' genome cannot diverge from that of the variant Mayinga (EBOV/May) by more than 10% at the nucleotide level for it to be considered an Ebola virus.

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