Tuesday, March 27, 2012

The phenomenon of the fleeing flu

Why is the common flu more deadly for some than it is for others? Everybody’s thought about it. How is it that some people can die from something that begins as a measly running nose, while others barely notice it come and go?

The vague answer would be ‘immunity’. At least that’s how I’ve always shut my brother up when he’s feeling inquisitive. But it’s always nice to understand ambiguities. Immunity is not a switch that can be at ‘good’ or ‘bad’ but a complex system governed by millions of pathways, enzymes, anatomical and external factors.

Researchers from a whole bunch of Universities and labs in the US and UK published an article in Nature on the 25th of March that might just have made a breakthrough of sorts in bringing some certainty into the hugely murky world of personalized medicine. Scientists from the Sanger Institute in Britain claim to have discovered the “crucial first line of defense” against the flu.

What they had to work with
In 2009 the journal Cell published a paper that established a protein called IFITM3 as having a crucial role in restricting viral replication, proving to be particularly hindrant to influenza, dengue and the West Nile virus. IFITM3 does this by inducing an immune agent called Interferon to prevent viruses from emptying their poison into cells, and consequently barring replication of the viral DNA in their host. See this for details.

However the study published in Cell was only demonstrated in-vitro, meaning in lab conditions. Usually an observed result only gains enough credibility to be applied once it is sufficiently replicated within a living system, or in-vivo.

It pays to play mice
The recent study from Nature have taken the IFITM3 study to the next level and proved that the IFITM3 does indeed play a highly significant role in determining how severely a flu virus affects its host. They did this by using one of the most efficient strategies to determine the functions of a gene/protein in a body. This involves deducing the role of substance ‘X’ in subject ‘Y’, for example, simply by observing the effect of Y in the absence of X. Since human subjects are not an option, the most commonly used animal model is Mus musculus or the house mouse(The mouse DNA is almost 85% similar to ours). Usually when the function of a gene, or its product -- a protein is to be determined, scientists genetically engineer mice with that particular gene absent or inactive so as to observe the effects. These mice are called knockout mice.

So these researchers used knockout mice which had an inactive IFITM3 gene and infected them with a low-pathogenicity (relatively mild) flu virus. They did the same for wild-type mice (normal variety) as well to compare the effects. They found out that the knockout mice suffered a great deal more than it’s wild cousins. The wild-type mice was tested and found to have increasing levels of the IFITM3 protein following infection, compared to the knockout mice which were unable to produce the protein. Similar results were seen when these two groups of mice were infected with the H1N1 virus which was recently responsible for the swine-flu pandemic.

The lungs of the mice without the protein (-/-) and with the protein (+/+) Image from Nature

From mouse to man
After collecting sufficient evidence of the protective role of IFITM3 in mice, the scientists proceeded to test their theory on human beings. How they did this is by examining influenza-ridden patients who have had to be hospitalized.

Now all human beings have the IFITM3 gene; the main differences lie within the gene itself. We’re all different from each other despite being more than 99% genetically similar. A large chunk of that variation is due to something called SNP’s or Single Nucleotide Polymorphisms.
SNP into it

Picture two chains of colour beads, each about 1200 beads long. The two chains are almost exactly identical except for example the 500th bead which is red in one chain but blue in the other. This would now be called rs500 (rs stands for reference SNP). And snp500 has two variants or alleles ie. R (red) and B (blue). In this analogy, the chain = IFITM3 gene, a bead = a nucleotide. Our cells are diploid, meaning we have two sets of each gene. So a person can either be RR (both red), BB (both blue) or RB (one of each). Of course in reality, our DNA is made of not color beads but nucleotides named A (adenine), G(guanine), C(cytosine) and T(thymine).

Example of an SNP. Image from Riken research.

Sometimes the type of SNP, or the variant that you have on a particular gene will markedly affect the kind of protein that gene produces. One particular variant (‘CC’) of an SNP called rs12252 on the IFITM3 gene, results in the formation of a shortened version of the usual IFITM3 protein. This ‘CC’ variant of this SNP is much less prevalent than the more popular ‘TT’ and ‘TC’. Now if the IFITM3-flu virus hypothesis is true, the shorter protein produced in people with ‘CC’ in their IFITM3 gene will not be enough to resist the flu virus, and such a person would be more likely to have a severe attack than a person who is able to produce the usual protein.

They tested the hypothesis by selecting patients from various hospitals who were struck with severe influenza and testing their DNA to detect whether they were TT, TC, or the rogue CC. Then they compared this distribution to the normal frequency of these alleles in the population and concluded that the faulty variant CC is indeed more prevalent in severe flu patients than it is in normal circumstances.

A pie chart representing how the rogue allele CC is more likely to occur in hospitalised flu patients than in the general European population Image from Nature.

Frankly my dear, should I give a damn?

This not only favours the hypothesis that the IFITM3 protein does indeed play a role in the progress of the flu, but also gives us a potentially useful way to predict a person’s susceptibility to a killer flu.

This also can explain why during the swine flu pandemic for example the virus was deadly for some and barely perturbed others.

With more confirmation, perhaps there could be a day when people can take informed decisions on whether or not he/she should take extra precautions like vaccines against the disease.

Even more in the future is the possibility of developing a drug that is similar to the IFITM3 protein so that it can curb the flu virus the same way.

But hold your horses…
There’s still a lot more to be done. The number of patients studied was only fifty three, hardly a large enough sample. The researchers themselves emphasise on the need for these results to be replicated in larger studies to hold good.

Another fact to keep in mind is that a living body is too complex for simple cause-effect relationships. Though the role of IFITM3 stands out, it is not the only gene that plays a role in our overall susceptibility to the disease. Other genetic and environment factors too interfere.

Other references

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