How Ebola Kills cover

How Ebola Kills

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Ebola virus has a mere 7 protein-encoding genes, but the RNA that is its genetic material holds hidden information. And yet this 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?


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How Ebola Kills

Pay Attention

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

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.

Eman is our son in the African sense, not based on DNA. Escalating panic pervades his emails of the past few days. The electronic communication is odd in the face of the crumbling infrastructure, the abandoned hospitals and schools. He taps on a phone, too terrified to enter an Internet cafe. And I’m mortified that the NBC nightly news placed a lengthy NASCAR crash report before an Ebola update. Eman wants to know why the US didn’t pay attention until the arrival here of two patients. So do I.

[Catalog and cover image:

Ebola Virus - Scanning electron micrograph of Ebola virus budding from the surface of a Vero cell (African green monkey kidney epithelial cell line). Credit: NIAID]

Eman Gokpolu (with Larry)

Eman Gokpolu (with Larry)

My African “son.”

He sends frequent updates from Liberia.

Look Close!

“That’s not Ebola!” I said to the vendor standing beside a display of boxer shorts festooned with pathogens, at a biology teachers conference a few years ago.

“No, that’s Ebola. Read the tag.”

“The tag’s wrong. It’s influenza. See the spokes on the surface? Ebola looks like a soup ladle.”

He didn’t believe me, but the website was corrected a few months later. I still have my faux Ebola shorts somewhere.

Ebola

Ebola

(Wikimedia Commons)

Just 7 Genes

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.

The irony of it all is stunning. Genetics and genomics journals bulge with ever-bigger data: 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...

How Does It Work?

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?

It turns out that the boxer shorts salesperson might have been unwittingly onto something – the way that Ebola replicates like mad while sabotaging the human immune response is similar to how the 1918 flu killed in not days, but hours.

An Ebola Timeline

Ebola virus homes to certain immune system cells and the boxy epithelial and endothelial cells that aggregate into layers.

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.

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.

Several Ebola

Several Ebola

Paradox

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, then 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.

Final Stage

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

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.

VP24 cuts off the host transcription factor STAT1, which is required to use gamma interferon, according to a report published yesterday 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.

Gamma Interferon

Gamma Interferon

The power of a virus such as Ebola is so astonishing that it

tends to evoke anthropomorphism. But the virus isn’t an enemy 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.”

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 enables the torn-apart endothelium to re-attach.

Consequence

Ebola 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. It’s 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 haven’t yet heard from Emmanuel today.

Ebola Awareness

Ebola Awareness

As a medical student Eman can’t treat patients, so he is a

“sensitizer,” educating people on how to avoid infection.

Update 8/17: Eman has a high fever, headache, and other worrisome symptoms, but assures me it is “just” typhoid. He reports that mostly NGO aid is getting to the people. The situation is much more desperate than US media suggest.

Update 8/20: I just got an email sent from Eman’s phone — from Joseph: “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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