Ebola

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Scientists in protective equipment testing animal samples for Ebola Virus. Photo Credit: Content Providers(s): CDC/ Ethleen Lloyd [Public domain], via Wikimedia Commons

Ebola virus (EBOV) is a highly pathogenic and deadly disease that has remained an enigma through the ages. Its high infection rate and mortality rate are extremely problematic since there is currently no vaccine or treatment for infection. We are currently experiencing the largest outbreak of EBOV in recorded human history. Extensive research on EBOV has shown that is largely effective because of how it induces massive immune system deregulation in infected humans.

Overview of Ebola Virus and Ebola Virus Infection

Ebola virus belongs to the Filoviridae viral family which has three identified genera that include Ebola virus, Marburg virus, and recently identified Cueva virus¹. The Ebolavirus genus itself has five identified species which include Reston Ebolavirus, Bundibugyo Ebolavirus, Sudan ebolavirus, Taı¨ Forest Ebolavirus, and Zaire Ebolavirus¹. In 1976 an outbreak of hemorrhagic fever in both Zaire and Sudan infected 550 individuals and was fatal in 430 of them^6,7. The virus responsible for the outbreak was isolated from the infected patients and was found to be morphologically similar to Marburg but it was also serologically distinct⁶. Even after multiple outbreaks of both Marburg and Ebola, and extensive research on the different strains that have caused those outbreaks, the origin of Filoviruses still remains a mystery⁶. Outbreaks of Filoviruses have usually been contained in remote areas of Central Africa⁷. However the world is currently experiencing the largest Ebolavirus outbreak in its history. The outbreak is affecting Guinea, Liberia, Sierra Leone and Nigeria⁷. Had no interventions taken place, it was estimated that 1.4 million cases could have occur in Liberia and Sierra Leone by the beginnings of 2015⁷.

Ebola virion as seen through transmission electron micrograph. By CDC/Cynthia Goldsmith [Public domain], via Wikimedia Commons

Morphology

Ebola can vary in length and observed optimal length as correlated to infectivity for is 970nm⁶. The individual virions can take many different shapes including long filaments, mace-shaped, ring, or U-shaped^6,7. The virus has a diameter of 80nm and contain a nucleopcapsid, an envelope derived from host cell plasma membrane budding, and a surface layer of glycoprotein trimers^6,7. EBOV is a linear negative-sense single stranded RNA virus⁶. EBOV is stable at room temperature, but can be inactivated by heating at 60˚C for thirty minutes, UV irradiation, commercial hypochlorite and phenolic disinfectants, and lipid solvents⁶.

Transmission and Host Invasion

Ebola virus zoonotic life cycle. By Centers for Disease Control and Prevention (CDC) [Public domain], via Wikimedia Commons

Ebola appears to be a zoonotic disease, yet the origin of the virus family still remains a mystery and no official reservoir has been identified^6,7. Current speculation points to rodent or bat reservoirs⁶. Data analysis suggest that fruit bats, such as Hypsignathus monstrosus, Epomops franqueti, Rousettus aegyptiacus and Myonycteris torquata may be the reservoir⁷. Filoviruses are transmitted through direct contact with infected (living or dead) animals^6,7. The viruses are also transmissible from person-to-person through direct or intimate contact with the infected individual or the individual’s bodily fluids^6,7.

Ebola can infect its hosts through breaks or abrasions in the skin, accidental injection, or through mucosal surfaces⁷. The entry process is thought to go through three phases which include cellular attachment, endocytosis, and fusion^1,7. It is strongly believed that Ebola enters the host cells by apoptotic mimicry and is consequently phagocytosed as part of micropinocytosis cellular response^1,7. Accordingly, it is speculated that Ebola entry into host cells is enhanced by its lack of needing a surface receptor for entrance^1,7. Humans are able to transmit EBOV as soon as symptoms begin to manifest⁷. The human body continues to be infectious throughout the course of the infection and even after death⁷. In the current Ebola outbreak, the majority of infected individuals range from ages 15 to 44 years of age². Incubation period of the infection is about 11.4 days, and the disease lasts about 15.3 days, and can end in either recovery or death². It is estimated that the current case fatality rate is 70.8%².

Symptoms of Ebola Infection

EBOV causes acute hemorrhagic fever and illness^4,6. The virus usually incubates between 4-10 days⁶. Post incubation the infected individual becomes abruptly ill while displaying unspecific symptoms such as severe headache, myalgia, fever, bradycardia, malaise, and conjunctivitis⁶. The patient quickly deteriorates over the next 2-3 days while experiencing severe nausea, pharyngitis, hematemesis, melena, prostration, and obtundation⁶. Further deterioration includes uncontrolled bleeding from visceral hemorrhagic effusions, as well as venipuncture sites⁶. Usually a maculopapular rash appears at around day 5, and death usually occurs 6-9 days after onset of the disease⁶.

Treatment

Currently there is no designated treatment for Ebola hemorrhagic fever⁶. An anti-viral drug that has been used to treat other hemorrhagic fever, Ribavirin, has shown no in vitro effect on EBOV, and is thus of little clinical value⁶. Passive immunity for other viral diseases has been provided to individuals suffering from an infection using human convalescent plasma; however efficacy has not been confirmed when used on patients suffering from EBOV infection⁶. The best care available to patients infected with EBOV is intensive supportive care to prevent shock, bacterial superinfection, hypoxia, hypotension, renal failure and cerebral edema⁶.

Ebola Evades the Immune System

Ebola viral protein VP24

Either Sudan Virus VP24 (SUDV1–233) or Ebola Virus VP24 (EBOV1–233) was coated onto the ELISA plate at 0.01 mg/ml. Plate was incubated with STAT1 and binding was detected with HRP conjugated secondary antibody and optical density was read at 450 nm. BSA was used as the negative control. Figure provided by Zhang, Adrianna, et al. PLOS Pathology

In a normal immune system response interferons (IFNs) trigger the protective defenses of the immune system to eliminate pathogens. IFNs activate Signal Transducers and Activators of Transcriptions (STAT) proteins, which in turn activate an immune response⁹. STAT1 is a crucial part of the Ebola viral infection pathway⁹. Normally STAT1 is phosphorylated when activated, and consequently is translocated to the nucleus via karyopherin-mediated nuclear trafficking⁹. Karyopherins, also known as importins, are responsible for the nuclear import of proteins that are too large for diffusion across the membrane, such as STAT1¹⁰. Karyopherins have specific structural features that allow them to participate in binding. Karyopherin-α (Kapα) consists of ten helical repeats that are called armadillos (ARMs)¹¹. ARMs 8-10 are important for Kapα binding to classical nuclear localization signal (cNLS)¹¹. It had been shown in previous studies that Zaire Ebola virus protein VP24 has the ability to bind to karyopherin α1, α5, or α6. Thus Ebola protein VP24 selectively inhibits IFN-induced gene expression by sequestering nuclear accumulation of phosphorylated STAT1 since Kapα cannot bind to and translocate STAT1¹². More recent research has shown that VP24 can also bind directly to STAT1, consequently blocking STAT1 translocation to the nucleus through two inhibitory mechanisms¹³. Zhang et al preformed an ELISA test to determine if Ebola virus VP24 or Sudan Virus VP24 could bind to purified STAT1¹³. It can be seen that there is a strong binding affinity between STAT1 and both versions of VP24 as compared to the negative control BSA ¹³.

Ebola uses apoptotic mimicry to invade cells

Figure provided by Reid, Patrick, et al. PLOS Pathology

Ebola Tetherin Angatonism

Figure provided by Gnirß, K., et al. Viruses

Further Reading

Novel Nucleoside Ebola Treatement-Nature article presenting research on potential Ebola treatement.

Top Ebola Facts- CDC page on Ebola Hemorrhagic Fever.

Ebola Outbreak Updates- Doctors Without Borders latest updates on the outbreak in West Africa.

References

1. Misasi, John, et al. Camouflage and Misdirection: The full-on Assault of Ebola Virus Disease. Cell. 2014, 159, 477-486.

2. WHO Ebola Response Team. Ebola Virus Disease in West Africa- The first 9 Months of the Epidemic and Forward Projections. The New England Journal of Medicine. 2014, 371, 1481-1495.

3. Warren, Travis, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature. 2014, 508, 402-405.

4. Caballero, Ignacio, et al. Lassa and Marburg viruses elicit distinct host transcriptional responses early after infection. BMC Genomics. 2014, 15, 1-12.

5. Shabman, Reed, et al. Deep Sequencing Identified Noncanonical Editing of Ebola and Marburg Virus RNAs in Infected Cells. American Society for Microbiology. 2014, 5, 1-11.

6. Beer, Brigitte, et al. Characteristics of Filoviridae: Marburg and Ebola Viruses. Naturwissenschaften. 1999, 86, 8-17.

7. Martines, Roosecelis, et al. Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg Viruses. The Journal of Pathology. 2014, 1-75.

8. Bausch, Daniel, et al. Treatment of Marburg and Ebola hemorrhagic fevers: A strategy for testing new drugs and vaccines under outbreak conditions. Elsevier. 2008, 78, 150-161.

9. Reich, Ling. Tracking STAT nuclear traffic. Molecular Genetics and Microbiology. 2006, 602-612.

10. Cook, Atlanta, et al. Structural Biology of Nucleocytoplasmic Transport. Annual Review of Biochemistry. 2007, 76, 647-71.

11. Chook, YuhMin, and Blobel, Günter. Karyopherins and nuclear import. Current Opinion in Structural Biology. 2011, 11:6, 703-715.

12. Reid, Patrick, et al. Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1. Journal of Virology. 2007, 13469-13477.

13. Zhang, Adrianna, et al. The Ebola Virus Interferon Antagonist VP24 Directly Binds STAT1 and Has a Novel, Pyramidal Fold. Plos Pathogens. 2013. 1-12.

14. Jemielity S, et al. TIM-family Proteins Promote Infection of Multiple Enveloped Viruses through Virion-associated Phosphatidylserine. PLoS. 2013, 9, 1-14.

Edited by Constanza Jackson, a student of Nora Sullivan in BIOL168L (Microbiology) in The Keck Science Department of the Claremont Colleges Spring 2014.