Ebola

No other disease has captured the modern imagination with such sensational horror as Ebola. The possibility of infection being transported into dense cities and the western world along with the possibility of bioterrorism captures our attention. However, much of the disease’s infamous reputation is due to sensationalized stories of the outbreaks along with the popular perception of the disease causing a disconcerting amount of bleeding from every orifice. In actuality, the disease’s outbreaks are relatively rare (although increasing) and the presentation itself only includes external bleeding in less than half of the cases. Still, with a mortality rate ranging between 40-90% and no current treatments, Ebola is not a disease to be taken lightly.

 Ebola virus

Meet the Virus

Ebola is caused by a filovirus known as Ebolavirus. Filoviruses are filamentous (filo- being derived from filum, Latin for thread) viruses[14]. The virus looks like a tangled thread with the loops sometimes being described (in a rather morbidly cute way) as reminiscent of Mickey Mouse’s head. Due to its high virulence and lack of treatment, the virus is categorized as a biodefense Class A pathogen, requiring biosafety level 4 handling [3,10,12]. Consequently, only a few laboratories in the world are equipped to study it.

 Ebola Virus Mickey

There are five known species of Ebolavirus, each with a distinct case fatality rate and well defined endemic area. The Zaire ebolavirus has the highest fatality rate, which falls between 60-90% (the current outbreak is a 70% fatality rate strain of the Zaire ebolavirus) and the Sudan ebolavirus’s fatality hovers between 40-60%. These two are the most common culprits of outbreaks. Bundibugyo ebolavirus carries a case fatality of less than 40%. The fourth species, whose name changed from the romantic sounding Côte d’Ivoire ebolavirus (Ivory Coast ebolavirus) to Taï Forest ebolavirus, has only infected one human that we know of, and the patient survived. Finally, Reston ebolavirus is cautiously considered nonpathogenic in humans – in other words, infected patients show no symptoms of disease, although their bodies produce antibodies against it [1,3,6,14].

The genome of Ebolavirus is made of RNA and only contains seven genes (we have 20-25 thousand protein coding genes, in comparison); a really small number considering the damage the virus causes. These seven genes each code for proteins: Nucleoprotein (multiple nucleoproteins encase the RNA to form the viral capsid), glycoprotein (proteins that dwell in the virus’s lipidmembrane envelope to bind it to cells), RNA-dependent RNA polymerase (the protein that catalyzes the replication of RNA, aka the baby maker of a virus), and four structural proteins known as VP24, VP30, VP25, and VP40. Scientists are still working on elucidating what these last four proteins are used for, although at least VP30 and VP35 are related to the transcription of Ebolavirus genes[3,15,16].

Feldmann_ViralStructure

Source: [4] Feldmann H, Jones S, Klenk H-D, Schnittler H-J. “Ebola virus: from discovery to vaccine.” Nature Reviews Immunology. 2003. 3.

 

The Ebolavirus exists in nature independently of humans. It dwells in reservoir species in Africa and the Phillipines; species which act as the long-term host and, consequently, do not present with fatal symptoms when carrying the disease. Scientists are still searching for these reservoir species of Ebola, although evidence suggests at least one host is the African fruit bat found in central and sub-Saharan Africa. Antibodies to Ebolavirus have been found in these fruit bats and they remain asymptomatic when infected[1,2.7,9].

When Ebolavirus is transferred from a reservoir host to a species that shows symptoms and has a tendency to die rather rapidly, this species is aptly known as the end host (or, if feeling especially morbid, “dead-end” hosts). Unfortunately, that’s us. ‘End’ or ‘dead-end’ actually refers to the virus being unable to persist in the species, as infected hosts either die too quickly to allow the virus to propagate through the population, or are inefficient at passing it on to other hosts.

This transfer is rare, yet bats are often hunted and consumed. This suggests that infection is either inefficient or infection is regulated by specific conditions such as scarcity of food, stress, or pregnancy that could all increase aggressive behavior within and between species, creating more opportunities for the virus to infect a new host[6,7]. It is more likely that humans catch it from other end hosts, specifically infected primates. Monkeys and apes play a role in the virus’s natural cycle, but we’re actually unsure if they are dead-end hosts (see the diagram with all the question marks below). Great apes in particular seem to have an unfortunately close relationship with the virus, especially the Zaire ebolavirus strain. Populations of western lowland gorillas and chimpanzees have decreased by up to 80% in areas of central Africa, and these disastrous population losses have been linked to Ebola[14]. Whether we pick it up from bats, apes, or an unknown host, outbreaks most frequently occur due to a single exposure followed by human-to-human infection[2].

Source:  [14] Olival K and Hayman D. “Filoviruses in bats: current knowledge and future directions.” Viruses. 2014. 6.

Source: [14] Olival K and Hayman D. “Filoviruses in bats: current knowledge and future directions.” Viruses. 2014. 6.

Transmission between humans occurs through the transmission of bodily fluids (including semen, genital secretions, and nasal secretions via direct contact or contaminated materials). Male survivors of Ebola can pass the virus onto a new host through semen for up to two months after recovery! The virus enters the new host through mucosal surfaces or breaks in the skin[3]. Most infections occur between family members or care givers, through contact with bodies during funeral preparations and proceedings, or in the health care setting to medical staff or other patients [10]. Many infections have also occurred from contaminated needles – in these cases, the fatality is much higher: in 1976, cases due to contaminated injections had 100% fatality, while contact infections resulted in 80% fatality[3,8].

Ebola

Ebola hand

Once the Ebolavirus infects us, we present with the disease known as Ebola (surprise!). It is suspected that many cases of Ebola may not be recognized, and there is often a lag time (months) between the initial case and actual detection of the virus, because the symptoms are mistaken for other, more common tropical infections. The initial presentation of the disease includes a fever and vomiting, which is also seen in the far more common culprits Malaria and Lassa fever[1,6,10]. You only need to check the news these days to see this problem: the number of people who have been quarantined and tested for Ebola due to presenting with a fever and vomiting, only to end up having something as innocuous as the flu, is wrecking media-scare havoc left and right.

After being exposed the virus incubates in humans for 4-10[2,6] or 2-21[3] days before any symptoms present. During this time, people are not infectious. The first symptoms may include a fever, chills, muscle pain, nausea, abdominal pain, vomiting, and diarrhea – all of which seem pretty similar to the common flu. Next, 5-7 days into the onset of symptoms, half of patients present with a macropapular rash. At the peak of the disease, the infamous bleeding (hemorrhagic) manifestations may develop, including bleeding from injection sites and mucosal membranes (eyes, nose, vaginal/rectal, gut – commonly seen in urine and feces). Bleeding under the skin can also cause bruising. Late stages may include shock, convulsions, and metabolic disturbances. Survivors begin to improve 6-11 days into the disease, while in fatal cases, death often occurs 6-16 days after onset. The cause of death in Ebola is not, in fact, the infamous bleeding. Instead, multiple organ failure and shock are the fatal culprits[2,3,6,8].

Ebola Pathogenesis

Let’s take a closer look at exactly what is going on to cause this rapid, terminal spiral of symptoms. Due to the difficulty in studying the Ebolavirus in action, scientists are still working to understand the exact pathogenesis. Here’s what we know:

Original source unknown

Original source unknown

First of all, the virus enters through lesions in the skin or through mucosal membranes. The virus infects a wide range of cells, but its primary targets are macrophages and dendritic cells, as well as late infection of endothelial cells[2,3,8]. Macrophages are white blood cells, specifically the ones that we commonly see in cartoons ‘eating’ pathogens in our blood (this is actually known as phagocytosis). Dendritic cells are also immune cells, but these help initiate and direct the immune response. Endothelial cells line blood vessels and lymphatic vessels. So, the virus sneaks in and spreads from the infection site into these cells, migrating to the lymph nodes and through the lymphatic system to spread the infection, particularly to the liver, spleen, and adrenal glands.

When the virus infects cells, it essentially hijacks the cell and forces it to become a virus-producing factory, churning out new copies of the virus. This results in a loss of natural function and eventual cellular death by apoptosis.

Infected immune cells release nitric oxide, a chemical used in cell communication to help mediate hypotension, which is a common symptom of Ebola. In high concentrations, the chemical also triggers the death of other immune cells, resulting in nearly all natural killer cells being destroyed by the fourth day of infection[3,4,8].

The loss of immune cells due to viral infection and apoptosis impairs the immune response and, additionally, it appears that the virus can actually suppress some immune responses to hinder the host overcoming the infection[5,7]. Despite this, infected cells still manage to release chemicals that induce an inflammatory response. Unfortunately, this ends up backfiring. The high concentration of the virus in endothelial cells results in cell damage and death in the walls of blood vessels. Combined with the host’s inflammatory response, the blood-tissue barrier becomes damaged and leads to hemorrhaging[3,4,5,8].

At the same time, infected immune cells and the inflammatory response cause the expression of tissue factor, which increases coagulation (blood clotting). This leads to disseminated intravascular coagulation, a condition where the proteins involved in controlling clotting become over active and eventually are used up, resulting in a lack of clotting control and increased risk of serious bleeding. Additionally, damage to the liver due infected cell death could result in decreased synthesis of coagulation and plasma proteins, triggering bleeding[3,4,5,8].

Cell damage to the adrenal cortex reduces control of blood pressure and the secretion of important enzymes, causing hypotension, sodium loss, and a decrease in blood plasma volume resulting in shock (similar to toxic shock). Combined with multiple organ failure caused by the damage to vascular and coagulation systems, the body eventually succumbs[3,4,5,8].

History

Ebola has almost exclusively occurred in Africa, with one strain being present in Asia and laboratory animal outbreaks occurring in the United States and Europe after importing monkeys from the Philippines.

Source: [1] Bausch D and Schwarz L. “Outbreak of Ebola virus disease in Guinea: where ecology meets economy.” PloS. 2014. 8(7).

Source: [1] Bausch D and Schwarz L. “Outbreak of Ebola virus disease in Guinea: where ecology meets economy.” PloS. 2014. 8(7).

The first known outbreaks of Ebolavirus took place in 1976, in southern Sudan and northern Zaire (now the Democratic Republic of the Congo). These outbreaks were caused by what became known as the Sudan ebolavirus and the Zaire ebolavirus, respectively. The reuse of contaminated needles played a large role in spreading the disease during these outbreaks, which resulted in 284 infections and 151 deaths[3].

In 1989 the Reston ebolavirus was discovered in Cynomolgus monkeys imported from the Philippines to a research facility in Reston, Virginia USA. The Philippines exports purpose-bred, non-human primates to be used in research worldwide. In the 1980’s and 1990’s over 5000 animals were exported per year. That number is now less than 1500 annually[11]. In the 1989 outbreak, Ebola spread through the facility’s monkey population by droplets and small particle aerosols, a potential airborne route that would cause significantly more distress if this strain actually caused symptoms in humans. Once the pathogen was identified as an Ebolavirus, the army’s USAMRIID branch sent people to the facility to euthanize all the monkeys and cleanse it. A similar outbreak occurred in monkeys imported to a lab in Sienna, Italy, in 1992-3, and again in the United States in 1996. In 2008, the disease was found in pigs in the Philippines, which raises the concerns for it entering the food chain[3,4,7,11].

The Taï Forest ebolavirus was discovered in 1994, after an ethnologist became infected while doing a necropsy on a chimpanzee[3].

In 2007, the latest species, the Bundibugyo ebolavirus, was discovered during an outbreak in Uganda.

Biological Warfare

As a Category A pathogen, Ebolavirus is considered a high risk agent and potential biological warfare agent. In 1993 the Aum Shinrikyo, a Japanese cult that sought to establish a theocratic state in Japan by proving an apocalyptic prophecy (along with other rather unhinged methods), attempted to obtain the Zaire ebolavirus from Africa with the intention of using it as a weapon[6a]. Fortunately, they failed.

 Ebola_biowarefare

Treatment

There is no current treatment for Ebola. Instead, strategies capitalize on managing the outbreak and symptoms: patients are to be isolated and symptoms treated. Intensive care treatment aiming to maintain blood volume and electrolyte balance and managing shock, kidney failure, coagulation disorders, and any secondary infections is paramount[2,3].

On the bright side, there are many investigational treatments being researched, and the current outbreak is pushing things along. Vaccinations are being explored, and their use would likely include ring vaccination during outbreaks to contain them, vaccinating health care providers and researchers, and/or vaccinating great apes to protect their populations and decrease the risk of the infection crossing into humans[7].

Many therapeutic agents are also in the works, with one example being T-705, which is the first effective agent that treats advanced Zaire ebolavirus – it prevented death in 100% of animals when given 6 days post infection, in a study published this year. The drug functions by inhibiting viral replication[13]. Hopefully this drug, along with others, will prove successful in further clinical trials!

 Ebola

References

[1] Bausch D and Schwarz L. “Outbreak of Ebola virus disease in Guinea: where ecology meets economy.” PloS. 2014. 8(7).

[2] Feldmann, Heinz. “Ebola – a growing threat?” The New England Journal of Medicine. 2014.

[3] Feldmann Heinz. “Ebola haemorrhagic fever.” Lancet. 2011. 377(9768).

[4] Feldmann H, Jones S, Klenk H-D, Schnittler H-J. “Ebola virus: from discovery to vaccine.” Nature Reviews Immunology. 2003. 3.

[5] Feng Z, Cerveny M, et al. “The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR.” Journal of Virology. 2007. 81(1).

[6] Groseth A, Feldmann H, Strong J. “The ecology of Ebola virus.” Trends in Microbiology. 2007. 15(9).

[6a] Hawley R and Eitzen E. “Biological weapons – a primer for microbiologists.” Annual Review Microbiology. 2001. 55.

[7] Hoenen T, Groseth A, Falzarano D, Feldmann H. “Current Ebola vaccines.” Expert Opinion on Biological Therapy. 2012. 12(7).

[8] Hoenen T, Groseth A, Falzarano D, Feldmann H. “Ebola virus: unraveling pathogenesis to combat a deadly disease.” Trends in Molecular Medicine. 2006. 12(5).

[9] Leroy E, et al. “Fruit bats as reservoirs of Ebola virus.” Nature. 2005, 438.

[10] MacNeil, A and Rollin P. “Ebola and Marburg hemorrhagic fevers: neglected tropical diseases?” PloS. 2012. 6(6).

[11] Miranda M and Miranda N. “Reston ebolavirus in humans and animals in the Philippines: a review.” Journal of Infectious Diseases. 2011. 204(3).

[12] Nakayama E and Saijo M. “Animal models for Ebola and Marburg virus infections.” Frontiers in Microbiology. 2013. 4.

[13] Oestereich L, Ludtke A, et al. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model.” Antiviral Research. 2014. 105.

[14] Olival K and Hayman D. “Filoviruses in bats: current knowledge and future directions.” Viruses. 2014. 6.

[15] Sanchez A, Trappier S, Mahy B, et al. “The virion glycoproteins of Ebolaviruses are encoded in two reading frames and are expressed through transcriptional editing.” Proceedings of the National Academy of Sciences USA. 1996. 93.

[16] Volchkov VE, Becker S, Volchkova VA, et al. “GP mRNA of Ebola virus is edited by the Ebola virus polymerase and by T7 and vaccinia virus polymerases.” Virology. 1995; 214.

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7 thoughts on “Ebola

  1. This was a nicely written (and timely) entry. You’ve presented some information that I have not seen elsewhere (the genetics, the entire section on pathogenesis, the commentary on “dead-end” hosts, and the information on how-long til death (or the beginning of recovery)).

    Some odds and ends that may be of interest to you:

    Dogs may be susceptible to Ebola infection, but the infection is asymptomatic. http://www.ncbi.nlm.nih.gov/pubmed/15757552 (I like dogs and we have a dog, so naturally I had to go find out about that.)

    There is a possibility that at least some Ebola strains (other than Reston) may be spread through droplets; see http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/ebola-eng.php “MODE OF TRANSMISSION”, and this 2012 paper on Zaire Ebola http://www.nature.com/srep/2012/121115/srep00811/full/srep00811.html . Note also that the
    CDC suggests that being within a few feet of someone contagious with Ebola poses a risk (low, but not non-zero) of infection; droplets are one suggested mode of transmission (see the footnote) http://www.cdc.gov/vhf/ebola/hcp/case-definition.html .

    There is an on-going forum thread monitoring news on the current Ebola outbreak (which they are calling “New Ebola” (I am under the impression it has been shown to be related to Zaire Ebola)); the link is to page 1 but the thread has now grown to 87 pages http://www.singtomeohmuse.com/viewtopic.php?t=5725 . (I am not a member of the PFI forum and just recently learned about it, so I can’t vouch for its sanity or validity; I am just throwing the link out there in case you might be interested in looking at it. (If there seems to be some confusion of information there, I think that at least partly stems from the chaos in and information (or lack thereof) from the affected W. African countries at this time. It was posted on another forum that one of the PFI forum moderators is a virologist, for what that’s worth.))

    • Thank you for all of these! I was just reading about the American doc who was being treated with ZMapp in Emory. He is being released from hospital soon.

      I’m not sure how much of the drug they will produce to be used without all the proper trials and approvals. Still, it is a promising beginning.

  2. I have not seen any confirmation of this on mainstream media, but according to this site (I have no opinion on its trustworthiness) it looks like the particular Ebola strain running wild in Liberia and neighboring West Africa has now been officially named the Mano River variant. http://sunsetinparadise.net/?p=80

    • It doesn’t look like the actual primary literature that site references is looking specifically at the latest Ebola outbreak cases, nor is it suggesting a name. “We investigated what other arthropod-borne and hemorrhagic fever viral diseases might be causing serious illness in the region and confounding the diagnosis of Lassa fever.” More of a survey of various viruses rather than a focused look at the outbreak. Not sure when samples were taken, but it is possible it was before this outbreak got rolling.

      They did find Ebola (see below), but this is unsurprising as one would expect undiagnosed Ebola cases in the population, as it often presents like the more common Malaria or Lassa.
      “We found evidence that SUDV was responsible for 1 infection but no evidence for TAFV infection, the only ebolavirus isolated in West Africa. In the ebolavirus PRNTs, we did not include the newest discovered ebolavirus, Bundibugyo virus, which cross-reacts with EBOV in immunoassays (26). Ebolavirus infections in Sierra Leone might be the result of Bundibugyo virus or an ebolavirus genetic variant and not EBOV.”

      • Yes, sorry, my bad. (I didn’t actually read the primary paper…)

        (Don’t post late at night… don’t post late at night… don’t post late at night…)

  3. …and now I am going to break my last rule (don’t post late at night), because I just read these and thought you might be interested:

    http://www.npr.org/blogs/goatsandsoda/2014/08/26/342451672/how-ebola-kills-you-its-not-the-virus (It’s by cytokine storm; that makes me wonder what an analysis of the age of the victims versus survival rates by age would show… would it show any particular age bracket (say, young adults) as being most susceptible to death by Ebola?)

    and

    http://www.npr.org/blogs/goatsandsoda/2014/08/28/343734184/ebola-is-rapidly-mutating-as-it-spreads-across-west-africa?utm_medium=RSS&utm_campaign=news (doesn’t sound like this is a good thing, at least insofar as developing vaccines and treatments go)

    and finally

    http://www.npr.org/blogs/goatsandsoda/2014/08/19/341468027/ebola-in-the-skies-how-the-virus-made-it-to-west-africa (interesting hypothesis…. and yeah, it was Zaire…)

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