Thursday, November 6, 2014

How to Survive Ebola: researchers find clues to explain how some people survive infection

On Sunday, I gave you folks a link to an article about how genes affect Ebola survival.  I decided to read a little bit more into it and do a full Ebola post, since this is actually a pretty interesting (and open access) study.

People have this idea that Ebola symptoms are a lot like what we saw in Outbreak.  But in the 2014 Ebola outbreak, only a minority (30-50%) of those afflicted have progressed into hemorrhagic fever.  There are different symptoms, including organ failure and shock, and different ways in which people succumb to them.  Some folks survive, while others don't.  It turns out that this is about more than simply luck.

Researchers often use mice to study the progression of diseases.  With Ebola, existing mice models don't produce the hallmark symptoms (hemorrhagic fever, delayed blood coagulation, disseminated intravascular coagulation, death from shock), and so researchers have had to use non-human primates to study the pathogenesis of this virus.  We also know that the variations in symptoms are not the result of mutations in the viral genome (because Ebola's genomic mutation rate is really slow), and so they are most likely a result of variations in the host genome and immune response.

The researchers, led by Dr. Michael Katze from the University of Washington, bred new strains of mice to test the role of an individual's genetic makeup on Ebola symptoms and severity.  This team had previously done similar studies examining host immune response and influenza severity and outcome.

After infecting the normal mice used to study Ebola, the authors found a range in mortality, from 25-100%, but no evidence of hemorrhagic fever.  When they tested the virus on their 47 new mouse strains, disease phenotypes ranged from complete resistance, to lethality, to hemorrhagic fever, and the normal mouse Ebola symptoms.  Taking these results, the researchers decided to look more in-depth on the hemorrhagic fever-susceptible (HFS) line and the resistant line.

Ebola gRNA levels in the spleen (A) and liver (B) of
infected resistant and susceptible mice.
Mice from both lines lost about 15% of their body weight over the first 5 days of infection.  The susceptible lines died within 5-6 days of infection, while resistant mice survived and recovered their original body weight within 14 days.  Within 5 days, the HFS line presented the classic (human) Ebola symptoms, including prolonged blood coagulation, internal hemorrhage, coffee-colored blood, splenomegaly, and liver softening (eww!) and discoloration.  These symptoms were not present in the resistant line, though both lines had the same level of viral RNA in their livers and spleens.

Liver staining for VP40 in resistant (E and F) and susceptible (G and H)
mice infected with Ebola.
By staining liver sections for VP40 (a viral matrix protein used in assembling viral particles into the larger virion), the authors observed that the resistant line of mice had much lower levels of the protein in their liver tissue.  This means that the resistant line was able to target VP40 in the liver protein during the immune response, while the susceptible strain was not.  The two lines also differed in which liver cells were affected.  The HFS line showed programmed cell death (apoptosis) in all types of liver cells, while in the resistant line only liver endothelial cells were affected.  Clearly, the resistant line's immune response was able to effectively protect the more crucial cells.

The HFS line also had elevated proteins involved in cell signalling (MAPK and ERK) and inflammatory response (NF-kB) one day after infection, which stimulate productive Ebola infection.  By day 3, inflammatory and apoptotic pathways were predominant.  By day 5, the expression of genes in the HFS line was completely different than that of the resistant line.  In particular, cell signalling proteins called endothelial tyrosine kinases (Tie1 and Tek) were consistently elevated in resistant mice.  These proteins target other proteins involved in blood coagulation, and are able to turn them on.  The elevated levels in resistant mice show that these particular proteins are especially important in surviving Ebola infection.  Variations in the DNA sequence of Tek were good predictors of the initial onset of weight loss after Ebola infection, but the authors don't expand on this because these are preliminary results.  Hopefully we'll be getting more information on this in the near-future.

Overall, survivors experienced higher expression of genes involved in blood vessel repair (both the mechanics and regulation), and the production of infection-fighting white blood cells.  Mortality from Ebola is usually the result of blood vessel inflammation and cell death.  While this study doesn't give us the option of finding out who could be more or less susceptible to Ebola, it does shed some light on the processes that allow some people to survive the devastating infection.  The mortality rate of the current Ebola outbreak is 71%.

So far, there have been 13 042 reported cases of Ebola, with 4 818 deaths as of November 2nd.

(and if you now need some cheering up, like I do, check out this video of a baby eating a lemon - classic!)

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