Update: How Ebola Kills

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Eman Gokpolu (with Larry) is my African "son." He sends frequent updates from Liberia.

Eman Gokpolu (with little Larry, named for my husband) is our African “son.” He sends frequent updates from Liberia.

UPDATE OCT. 7:  Emmanuel (my “son”) and his family, in Liberia, are still all healthy! The post below is from mid-August, when much of the US still didn’t care about Ebola because it wasn’t here. It includes the immune system basics that rarely make it into media coverage.

Sunday, August 17:

Eman’s emails arrive hours ahead of the news here.

“An Ebola quarantine site was  attacked and looted. News is that most of the patients have escaped. This is going to put more fear into the population. All this because people are denying the virus.  More people might get exposed.  I’m so weak I can’t wake up this morning. Its 6:00 pm and I am still in bed listening to the news.  All this happened in a very populated area called West Point. Got pain all over my body. Keep me in your meditations.”

As a medical student Eman can't treat people, so he is a  "sensitizer," educating people on how to avoid infection.

As a medical student Eman can’t treat people. Instead, he is a “sensitizer,” educating people on how to avoid infection.

Emmanuel is a medical student in Liberia whom my husband and I have been supporting since he contacted me after reading my human genetics textbook in 2007. Until the fever hit him last weekend, he dedicated himself to “sensitization,” educating the public about how to stay safe. But now he’s too sick and weak to venture out.

His email from Monday, August 18, said only “Need help!

Eman is our son in the African sense, not based on his DNA. And our families have grown close. Some of the funds we sent to see him through medical school helped put his mother through nursing school. It costs a fraction of medical education here.

The emails and texts from Liberia are eerie in the face of the crumbling infrastructure, the abandoned hospitals and schools. Eman taps on a phone these days, too terrified to use an Internet cafe as he has in the past. We know he’s in trouble when his brother Joseph takes over — it means Eman is in the hospital. It’s happened for cholera, amoebiasis, and cerebral malaria more than once. Fighting infection is a way of life in Liberia.

I’m mortified when the news here focuses on the deaths of individuals — tragic as they may be — while the populations of African nations like Liberia, of the entire continent, are under threat. Eman wants to know why the US didn’t pay attention until the arrival here of two patients, who were treated. So do I.

JUST 7 GENES

The stark seeming-simplicity of the Ebola virus flashes across my mind whenever I receive an email from Eman.

Ebola virus has a mere 7 protein-encoding genes, but the RNA that is its genetic material holds hidden information. One key gene (GP, for glycoprotein) has an overlapping reading frame so that an alternate form harbors a stretch of added adenines. And the encoded protein is cut after translation, generating a mature secreted form that sits on the surfaces of viral particles, as well as a sugar-coated smaller part, like a moon carved from a planet.

(Wikimedia Commons)

(Wikimedia Commons)

The irony of it all is stunning. Genetics and genomics journals overflow with data. Always more exomes, more genomes, meta-analyses of meta-analyses that search for meaning among the nearly limitless combinations of variants of our 20,000 or so genes. And yet a 7-gene “infectious particle,” so streamlined it isn’t even a cell, isn’t even alive, can reduce a human body to a puddle, inner barriers dissolving into nothingness, within days.

How does Ebola virus, so much simpler than influenza, than HIV, do it?

AN EBOLA TIMELINE
Ebola virus homes to certain immune system cells as well as the boxy epithelial cells that aggregate into layers and the single bathroom-tile-like endothelial cells. Inside the body, the virus first tackles innate immunity – the immediate and generalized response to infection. Ebola commandeers monocytes and macrophages, the wandering cells that travel around the body, dividing, distributing its deadly cargo.

Meanwhile, the virus replicates like crazy.

(Wikimedia Commons)

(Wikimedia Commons)

In those who will not survive, the innate immune response goes on a tad too long. The virus also invades dendritic cells. These are the sentries that “present” the pathogen’s provoking antigens to the parts of the immune system that carry out the second phase, the slower and targeted adaptive response. And indirectly, mysteriously, lymphocytes die en masse, instead of producing antibodies.

Yet at the same time, a “cytokine storm” erupts, sending other arms of the immune response into overdrive. Levels of gamma interferon, interleukins 2 and 10, and tumor necrosis factor soar, triggering fever and flu-like symptoms. Yet it’s as if there’s no interferon at all. Viruses do not see it.

The bizarre immune response during Ebola infection is rightfully termed “paradoxical,” at once too slow, too little, too intense.

Then the body’s barriers begin to break down.

The endothelial cells that curl into the tiny tubes that are the capillaries, and also line the interiors of larger blood vessels, contort into blobs. Holes appear. Barriers melt away, and the fluids that they contained redistribute. The still-crazily-replicating virus now has direct access to organs, favoring the adrenal cortex (plunging blood pressure), the kidneys, gonads, spleen, and most dangerous, the liver.

(Wikimedia)

(Wikimedia)

The final stage is the bleeding, as the liver’s output of clotting factors becomes unhinged. One protein in particular goes by various names: in the older literature it’s simply “tissue factor,” but is also known as thromboplastin, CD142, and factor III.

Whatever it’s called, this cell surface glycoprotein converts prothrombin into thrombin, the essential final step in blood clotting. The fact that no deficiency of thromboplastin is known – the others cause hemophilias and other clotting disorders – belies its importance.

In Ebola infection, thromboplastin is too active, ushering in disseminated intravascular coagulation. Tiny clots form in blood vessels everywhere. Organ necrosis sets in as the blood supply ebbs, and clotting factors needed to stanch greater breaches as the blood vessels come apart become depleted. Hemorrhaging begins as the biochemical balance so critical to appropriate clotting vanishes.

Nicotiana benthamiana, the tobacco plant in which ZMapp is made. Thanks, GMOs!

Nicotiana benthamiana, the tobacco plant in which ZMapp is made. Thanks, GMOs!

BACK TO THE GENES
A human body overwhelmed with Ebola virus is like a castle whose defenses fail, from the inside out, all orchestrated by that puzzling handful of genes.

GP targets the virus to certain cell types, deforms the endothelium, and destroys antigen presentation. ZMapp, the drug being given to a handful of infected people ahead of human testing because it worked in macaques, counters GP. It consists of three monoclonal antibodies produced in tobacco cells.

Gamma interferon

Gamma interferon

VP24 cuts off the host transcription factor STAT1, which is required to use gamma interferon, according to a recent report in Cell Host & Microbe. And VP40 protein, because it forms the outside of the virus, should elicit an antibody response, only it usually doesn’t.

The power of a virus such as Ebola tends to evoke anthropomorphism. But the virus isn’t intentionally trying to kill people, as one prominent researcher told the New York Times, calling the virus “a survivor. It does what it can to avoid the human immune system.” It doesn’t think.

Another type of survivor might provide the clues necessary to stop the current epidemic: people whose immune systems can fight off the virus.

LEARNING FROM SURVIVORS
Just as HIV antivirals were developed using clues from people who never became infected despite repeated exposure, a solution to Ebola hemorrhagic fever might lie among individuals who recover.

Survivors have 10 million viruses per milliliter of blood serum; people who succumb have 10 billion. So far we know that the immune response in people who survive is subtly distinctive, the innate response turning off at a specific point and the adaptive response beginning in time to help, neither becoming overactive. Identifying biomarkers may reveal the specifics that drive resistance, such as an adhesion factor that re-attaches torn endothelium.

eman gradEbola hemorrhagic fever is the consequence of runaway viral replication against a backdrop of a strangely deranged immune response. We know the viral genome sequence, and I’m sure the genome sequences of survivors are being or will soon be sequenced. I hope it is only a matter of time until researchers deduce how variations of the 20,000-gene human genome or its expression resist the 7-gene genome of Ebola virus, and figure out how to replicate the response.

Until they do, I’m petrified. I just got an email sent from Eman’s phone — from Joseph, August 20.

“Eman walked to the hospital today because according to him, he is not doing well. He called me up in pain. Luckily, its not Ebola. We were so scared. He’s admitted. No word yet. I will keep you informed. Joseph”

Update Sunday August 24: Eman is still in the hospital, but he “only” has hookworms and malaria (which he always seems to have). When he gets out tomorrow, he plans to volunteer with MSF to fight Ebola.

 

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Update: How Ebola Kills by DNA Science Blog, unless otherwise expressly stated, is licensed under a Creative Commons Attribution 3.0 Unported License.

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15 Responses to Update: How Ebola Kills

  1. Rashon Fuller says:

    Greetings,
    First of all my hat off to you for this information very excellent.. I have a question what do you mean when you say Ebola 7 gene virus isn’t even a cell and is not alive? How does it look to survive and attach itself to roaming cells?thank you look forward to your response

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    • Ricki Lewis says:

      Technically the fundamental unit of life is a cell. A virus isn’t a cell — it is just a nucleic acid (DNA or RNA) in a protein or glycoprotein coat. It attaches to receptors on cells, enters, and deposits its genetic material, which the cell then uses to make viral proteins, and eventually new viruses burst out of the cell. A virus is considered an “infectious particle,” and not an organism. But many writers, such as in the current New Yorker, call a virus an organism. When I write my textbooks, I do not call a virus alive because it isn’t a cell. But really, this is all semantics. I too am puzzled by how something so small can do so much damage, not matter what we call it. Thanks for posting!

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  2. Pingback: Ebola | science in a teacup

  3. Rashon Fuller says:

    Thank you for your response.. I have one more question. How is it that this Ebola virus can maintain it’s active infectious state so long after the host cells or body is deceased? How is the fluids so highly contagious without a living cell to host it.. I only hear of this virus in relation to its human exploits where else in nature do we find this oh so destructive virus?

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  4. AriB says:

    Thank you for such an informative article. I do hope that things shape up for Eman and his family as well as yours by extension.

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  5. I have done some testing on viruses and bacteria on myself,but I have an advantage I have been studing ” Iridology ” for about 20 years on my on body so I can tell what works and what doesn’t. I have used colloidal silver as a first line of defense by starting with a teaspoon to up to 3 ozs. A day it takes up to 50 days to get into my system. Now think about all the things they use silver for, they tell you it doesn’t work , but does. The medicial field doesn’t want anyone to know this. I was in contact with

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  6. Alisa Delgado says:

    The people of West Africa fight illnesses every day in their tribes and cities. Their mortality rate is so high that in some tribes in Nigeria it is a custom to not name their children for eight days in case the newborn succumbs to an illness and passes. These babies get a name for each day they live and then a ceremony is performed and the family celebrates the life and the child is presented to the tribe. Human life who decides its value? For centuries America has been able to provide to our own country vaccines and medications to prevent and cure the same illnesses battled in West Africa. We have used healthy volunteers purposely injected with illnesses for testing to create treatments and save lives. A lot of people are hesitant in providing aid to foreign countries and think what happens over there can stay over there. With the Ebola virus outbreak, which the United States considers a biological global threat, in West Africa. I think our national opinion of having to test, retest and use healthy people needs to be reconsidered and the ZMapp and other serums should be given to those who have limited access to adequate health care and they should be allowed to try the serum our doctors have created to have a chance at living.
    The current outbreak has been recalculated from a 90 percent fatality rate down to a 47 percent according to WHO, The World Health Organization, website as of August 27, 2014 (WHO, 2014). With our advancements in medicine and the funding of finding a cure or treatment for Ebola. Our pharmaceutical companies have created a passive immune serum using tobacco plants. One such serum is called ZMapp and has been proven to save monkeys infected with the virus. This serum has not passed clinical phase one trials. We hadn’t purposely infected humans with Ebola and then given them the serum to see the side effects and other potential harms or benefits. The United States did give the serum to two American workers through an organization called Samarian’s Purse and they lived, and yet Doctors Without Borders declined giving it to their workers based on the U.S ethics policy of ‘do no harm,’ (S. Dilorenzo, M. Chang, Bakersfield Californian, 2014).
    In my opinion it is harmful to deny medical treatment based on a fear of side effects when death is imminent. Our own ethics policy becomes a moot point when there is so much global travel between our countries and the potential of spreading an illness that has an incubation period of anywhere from 2 to 21 days. With average travel time between our country and theirs is three days an infected person can begin their journey and arrive anywhere in the world with no outward symptoms. I would like to see our country put aside its fear of what may happen in the long run and place value given on the fact that these serums give the possibility of giving these people one more day with their families, one more day to celebrate a life. Life is something very endearing to the people of Africa, Faced with their mortality from birth I would like our country to offer the people of Africa the option to be our volunteers to use these serums and see if we can using it as a starting point to even more opportunities of helping a continent maybe advance to where malaria and hookworm are no longer the norm. The people of Africa are mothers, brothers, fathers, aunts, uncles. If in America faced with the same option of losing a large portion of a family I believe a lot of people would be lining up to get the shot just as we do now with the smallpox vaccine or the flu shot.

    References
    S., & Dilorenzo Cheng, M. (2014, August 14). Doctors: Ebola drug poses ‘impossible dilemma’ Bakersfield Californian, p. 41.
    Ebola virus disease. (n.d.). Retrieved August 28, 2014, from http://www.who.int/csr/disease/ebola/en/

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    • Thanks Elisa so much for sharing this info. I’ve been in the hospital myself so couldn’t monitor the comments until now. I really appreciate this important viewpoint on how best to use experimental medical resources.

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  7. sam says:

    3 REASONS WHY YOU SHOULD NOT FEAR #Ebola http://wp.me/p4bJip-4I
    A MUST READ!

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  8. Paul says:

    Thank you for the post. It’s great. I recently looked into this virus because of the concern of so many people. I think that this virus has the potential to spread because of the many ways that people can catch it. What are people currently doing to stop this virus? Is the a vaccine or cure available at the moment?

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    • The treatments and vaccines are all still in development, although the current crisis has certainly sped testing. A previous comment discusses the issue of accelerating from preclinical (animal) testing to testing in humans in Africa right away. Yes, Ebola is terrifying. The idea that it can’t come to the US is simply crazy. Emmanuel is doing well this week. He is healthy, and has volunteered with MSF while he awaits resumption of medical school. Thanks for posting!

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  9. Ricki, how is this ebola virus (nucleic acid) end up with a coating of protein or glycoprotein and is it the protein that actually attaches to the living cell.

    I also noticed that ZMapp had proteins in it also.

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    • A virus is a nucleic acid in a protein coat. The genetic material of the virus (RNA or DNA) includes the information for those outer (capsid) proteins. So when a virus injects its genetic material into a host cell, the host cell’s protein synthetic machinery makes the viruses proteins. Those proteins encapsulate the viral genetic material, and new whole proteins burst from the cell. Viral genetic material may be DNA or RNA.

      ZMapp consists of monoclonal antibodies. Antibodies are proteins.

      Hope that helps!

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  10. Hope soon as they can find a cure for this virus!

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