Filovirus
1. Classification
a. Higher order taxa
Virus; ssRNA negative strand viruses; Mononegavirales; Filoviridae
b. Genera
Marburgvirus, Ebolavirus
c. Species
Lake Victoria marburgvirus, Sudan ebolavirus, Zaire ebolavirus, Taï Forest ebolavirus, Reston ebolavirus, Bundibugyo ebolavirus
2. Description and significance
Filoviruses, including Marburgvirus and Ebolavirus, are branched from the family Filoviridae (1). Filoviruses cause viral hemorrhagic fever, a highly fatal disease in humans and primates characterized by internal or external bleeding (2). There are five species of Ebolavirus that have been discovered: Zaire ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, Reston ebolavirus, and Bundibugyo ebolavirus (2). The first Ebolavirus was discovered in Central Africa in 1976, and it was named after the Ebola River in Congo (2). Marburg was first found in Germany in 1967 while researchers were handling tissues from green monkeys (3).
Both Ebolavirus and Marburgvirus are transmitted through direct contact with bodily fluids such as blood from infected individuals or animals, and even through materials that are contaminated with such fluids. Symptoms of both viruses are severe: vomiting, bleeding from the skin and internal organs, organs losing function, and ultimately death (4). The incubation period, the time it takes for symptoms to appear from infection, for Ebola virus ranges from 3-12 days, while the incubation period for Marburg virus is 5-9 days (5).
In West Africa in 2014, there was an Ebola outbreak that spread all over the world, infecting 1,134 individuals. Exposure to the virus led to the deaths of many patients and health care workers (4). Outbreaks and epidemics of filoviruses are common, and researchers are continuously working on finding cures. Even though filoviruses have been classified as Risk Group 4 by the World Health Organization’s Biosafety Levels, there are currently no treatments available for humans (6).
3. Genome structure
The Filoviridae family contains negative-stranded RNA (7). The viral genomes are about 19kb long (7). Each virus particle contains 7 genes that encode for the functional proteins nucleoprotein (NP), virion protein (VP) 35, VP40, glycoprotein (GP), VP30, VP24 and the polymerase (L) (7).
Filoviridae family members are filamentous viruses that are enclosed by lipid membrane envelopes and are non-segmented (7). The Marburg virus is 790 nm long and the Ebolavirus is 970 nm long. The RNA genome is enclosed by the nucleoprotein (8). All the viral proteins are contained within the viral envelope. GP is a transmembrane protein, the only protein that is exposed on the surface of the particle; it functions as an attachment and fusion protein to gain entry into host cells (7). Tube-shaped nucleocapsids are formed during the viral replication cycle (8). The GP is important to engineering a vaccine for Filoviridae viruses (7).
VP40 is responsible for viral particle formation and budding and participates in viral or host cell metabolism during the viral replication cycle (9). The Filoviridae family relies on host metabolic machinery for replication, as the viral particles do not have independent metabolic capacities.
4. Pathology
Marburgvirus’s reservoir species is the fruit bat, Rousettus aegyptiacus. R. aegyptiacus is capable of sustaining the virus long-term, which maintains the virus’s potential to infect humans who ultimately experience the lethal effects of the virus (8). This finding lends support to the notion that fruit bats are generally the reservoir species for all Filoviridae viruses. In equatorial Africa, such bats are often encountered by humans and are even targeted for hunting, which shows that the virus may exist asymptomatically in bats with minimal rates of transmissions. Stimuli such as stress and co-infection may activate the virus, inducing it to cause symptoms and be more readily transmitted from bats to humans (8).
The Ebola virus enters a host via breaks in the skin, mucosal surfaces, or parental introduction. It is primarily spread through direct contact with infected bodily fluids such as blood, nasal, or genital secretions (8). The cellular machinery of many immune cells, such as monocytes, and epithelial cells is co-opted by viral particles and used for replication of the viral genome (8). Such cells assist in spreading the virus to lymph nodes, the liver, and the spleen of the host organism. Immune cells that have been infiltrated with viral particles migrate out of the spleen and lymph nodes, and spread to other body tissues (8). The liver and adrenal glands are targeted by the viruses, and the virus causes hepatocellular necrosis, which in turn reduces coagulation and the formation of plasma proteins, ultimately leading to the mass hemorrhaging that is experienced by Ebola patients (8).
5. Current Research
Despite there currently being no licensed vaccination or treatment for Ebola Virus or Marburg Virus, progress is being made towards preventing the viruses and treating the diseases the viruses cause (10). Two of the most common animal models for testing experimental vaccines are non-primate models such as mice, guinea pigs, and rabbits, as well as nonhuman primates (NHP) models (2). Non-primate models have genomic variability, but NHP genomes are more closely related to the human genome. Almost all current research is done using non-primate and NHP models. There are four main types of vaccines that are currently ready to be tested on humans after testing on non-primates and NHPs:
a. Venezuelan equine encephalitis virus replicons vaccine
The replicon vaccine uses an alphavirus as a vector by incorporating the gene of interest into the viral RNA (2). The vaccine has been tested on both non-primates and NHPs, and the results show that immunity was stimulated in NHPs. While the replicon vaccine can achieve a complete protection in both types of models against the Marburg virus, it does not protect both non-primates and NHPs from Ebola virus (2).
b. DNA-based vaccines
DNA-based vaccines use plasmids as vectors in primates, and are effective for evolving pathogens, such as Ebola virus. Because viral genome tends to evolve rapidly, DNA-based vaccine can change accordingly, defeating the virus regardless of its change in genome (11). DNA-based vaccines have mild adverse effects and can be produced on a large scale (2). Additionally, DNA vaccines can trigger a robust immune response in NHPs, though further testing is required to draw a final statistically significant conclusion (11). This type of vaccine is more effective on non-primates than on NHPs (2). Similar to the Venezuelan equine encephalitis virus replicons vaccine, DNA-based vaccines are more effective against Marburg virus than Ebola virus (2).
c. Adenovirus vaccine
The Adenovirus vaccine has a high transduction efficiency that can easily generate a higher level of immune response (2). However, the side effects of this vaccine are severe, including fever and headache, and the efficiency of the vaccine can be affected by the individual’s previous exposure to the virus (12, 13). In order to have a robust immune response, the subject has to have two shots. Despite the limitations this vaccine has, there is a new generation of researchers that aims to reduce the side effects (12).
d. Vesicular stomatitis virus (VSV) vaccin
With a single injection, the VSV vaccine triggers a robust humoral and cellular response in the human body, and results in mucosal and systemic immune responses (2, 15). Unlike the Adenovirus vaccine, VSV vaccines can work effectively regardless of whether the infected individual has had previous exposure to the viruses (15). Data has shown that even with late injection of the vaccine, such as after exposure, individuals can still have a substantial chance of survival (13). Though there are minor side effects associated with VSV vaccine, there are no toxic substances that remain in vaccinated NHPs following immunization (2, 13).
e. Virus-like particles vaccine
The virus-like particles vaccine mimics the mechanism of viruses to trigger immune responses in the human body (7). One main feature of the virus-like particles vaccine is its ability to be effective against multiple strains of the filovirus in one shot (15). The vaccine has shown to be sufficient to fight against both Marburg and Ebola virus, but if the vaccine fails in the particular individual, death may be accelerated (15). Moreover, the virus-like particle vaccine can work regardless of previous exposure to the filovirus and can work with the same effectiveness on both adults and children (16).
f. Whole-Virus Vaccine
Besides the traditional methods of producing vaccines as previously mentioned, there is a new approach to creating vaccines, and the result is the whole virus vaccine. The basic mechanism of the whole virus vaccine is to use gamma radiation or hydrogen peroxide to inactivate viral replication processes, but inactivated viral particles to generate an immune response (17). For more information, consult “An Ebola whole-virus vaccine is protective in nonhuman primates (17).”
g. Anticoagulant Treatment
Anticoagulant treatment, a method distinct from immunization, has also been proposed to treat Filoviruses and is based on the idea that the Ebola infection causes a dysregulation of lymphocyte and intravascular coagulation activation in the human body (18). Controlling the gene expression of lymphocytes and genes related to intravascular coagulation may lead to afflicted individuals having a greater chance of surviving infection (18). This treatment has been tested on NHPs, and 33% of infected NHPs have shown significant improvement (18). Further research can be done to test the efficacy of this treatment on humans.
9. References
1. Feldmann H, Geisbert TW, Jahrling PB, et al. Filoviridae. In: Fauquet C, Mayo MA, Maniloff J, Desselberger U, Ball LA, editors. Virus taxonomy: VIIIth report of the international committee on taxonomy of viruses. London: Elsevier/Academic Press; 2004. pp. 645–653.
2. Filovirus, Encyclopedia Britannica, Encyclopedia Britannica. Inc., 30 April 2017.
3. Hartman AL, Towner JS, Nichol ST (2010). Ebola and Marburg hemorrhagic fever, Clin Lab Med, vol. 30 (pg. 161-77)
4. Cook, N., Salaam-Blyther, T. Ebola: 2014 Outbreak in West Africa, Congressional Research Service In Focus, 2014
5. Mark G. Kortepeter, Daniel G. Bausch, Mike Bray (2011). Basic Clinical and Laboratory Features of Filoviral Hemorrhagic Fever, The Journal of Infectious Diseases, vol. 204, 810–816
6. Mulhlberger, E. (2007). Filovirus replication and transcription. Future Virology. 2(2), 205-215
7. Geisbert, T., Bausch, D., & Feldmann, H. (2010). Prospects for immunization against Marburg and Ebola viruses. Reviews in Medical Virology, 20(6), 344-357.
8. Feldmann, H. & Geisbert, T. W. (2011). Ebola hemorrhagic fever. The Lancet, 377(9768), 849-862.
9. Ascenzi, Bocedi, Heptonstall, Capobianchi, Caro, Mastrangelo, Bolognesi, & Ippolito. (2008). Ebolavirus and Marburgvirus: Insight the Filoviridae family. Molecular Aspects of Medicine, 29(3), 151-185.
10. Geisbert, T., Strong, J., & Feldmann, H. (2015). Considerations in the Use of Nonhuman Primate Models of Ebola Virus and Marburg Virus Infection. The Journal of Infectious Diseases, 212(Suppl2), S91-S97.
11. Geisbert, Thomas W., Bailey, Michael, Geisbert, Joan B., Asiedu, Clement, Roederer, Mario, Grazia-Pau, Maria, Sullivan, Nancy J. (2010). Vector Choice Determines Immunogenicity and Potency of Genetic Vaccines against Angola Marburg Virus in Nonhuman Primates. The Journal of Virology, 84(19), 10386-94.
12. Jacobs, Langland, Kibler, Denzler, White, Holechek, Baskin. (2009). Vaccinia virus vaccines: Past, present and future. Antiviral Research, 84(1), 1-13.
13. Geisbert, Thomas W, Hensley, Lisa E, Geisbert, Joan B, Leung, Anders, Johnson, Joshua C, Grolla, Allen, & Feldmann, Heinz. (2010).
14. Geisbert, Thomas W., Geisbert, Joan B., Leung, Anders, Daddario-DiCaprio, Kathleen M., Hensley, Lisa E., Grolla, Allen, & Feldmann, Heinz. (2009). Single-Injection Vaccine Protects Nonhuman Primates against Infection with 15. Marburg Virus and Three Species of Ebola Virus. The Journal of Virology, 83(14), 7296-304.
15. Swenson, Warfield, Negley, Schmaljohn, Aman, & Bavari. (2005). Virus-like particles exhibit potential as a pan-filovirus vaccine for both Ebola and Marburg viral infections. Vaccine, 23(23), 3033-3042.
16. Bukreyev, Dinapoli, Yang, Murphy, & Collins. (2010). Mucosal parainfluenza virus-vectored vaccine against Ebola virus replicates in the respiratory tract of vector-immune monkeys and is immunogenic. Virology, 399(2), 290-298.
17. Marzi, Andrea, Halfmann, Peter, Hill-Batorski, Lindsay, Feldmann, Friederike, Shupert, W Lesley, Neumann, Gabriele, . . . Kawaoka, Yoshihiro. (2015). Vaccines. An Ebola whole-virus vaccine is protective in nonhuman primates. Science (New York, N.Y.), 348(6233), 439-42.
18. Garamszegi, S., Yen, J., Honko, A., Geisbert, J., Rubins, K., Xia, T., . . . Mcelroy, Anita K. (2014). Transcriptional Correlates of Disease Outcome in Anticoagulant-Treated Non-Human Primates Infected with Ebolavirus (Transcriptional Correlates of Survival Following Ebolavirus Infection). 8(7), E3061.
