The technology we have available to us today in the lab is both a boon and a bafflement. Example: The screens we have for RNA expression in cells is so sensitive we can see tiny changes in RNA expression levels in healthy/diseased/drug treated/etc cells. YAY! More information! More observations! More new ideas for research!… Except, the screens we have for RNA expression in cells is so sensitive, we can see tiny changes in RNA expression levels that dont really mean anything.
Example: The techniques we have for identifying viral RNA/DNA in cells is so sensitive… that we can pick up scant bits of contaminating DNA.
Another example: We can do all kinds of protocols for seeing differences in susceptible/non-susceptible cells for different viruses, to figure out which genes are stopping the virus, thus we learn more about the biochemistry of the virus and new angles to attack it in patients… but these screens ID genes. They dont ID what exactly is going on. So we have huge lists of genes that are up/down regulated in cells that successfully fend off, say, influenza, but we dont know what it means. We can see the trees, but not the forest.
An example of one of these IDed genes is Interferon-induced transmembrane protein 3 (:-/) We knew IFITM3 was part of the innate immune response (not antibodies or your T-cells, which learn and evolve in response to pathogens– your innate immune response sees patterns and reacts only to those patterns). And in in vitro studies, they found IFITM3 to be related to resistance to Influenza, West Nile, and Dengue infection… but we didnt really know what that meant for Influenza, West Nile, and Dengue victims. In vitro and in vivo are different worlds.
This recent paper in Nature tried to resolve that:
First, mouse models. They generated mice that lacked the IFITM3 gene, then infected them with a low-pathogenicity murine-adapted H3N2 virus. This virus should not have given the mice any trouble.
And the regular mice did do fine. They lost a little weight for a bit, but they recovered. When the scientists looked at IFITM3 expression over time, it increased in the regular mice post infection.
The IFITM3(-) mice however, had real rough time with this weakened virus. They showed symptoms one would expect form a virulent virus, like high levels of influenza replication in the lungs, losing lots of weight, and generally having a rough time. From a virus that basically did nothing to the normal mice.
They saw the same pattern with several other forms of influenza in their mouse model, including Swine Flu.
Well, neat. Now we know how to kill IFITM3(-) mice.
The question remains as to whether/how IFITM3 plays a role in influenza infections in humans.
So, these folks looked at the IFITM3 gene in 53 people who got sick enough from Swine Flu that they had to be admitted to the hospital. Most of these people had a ‘normal’ IFITM3 gene with a TT at a splice acceptor site, or a variant commonly found in the general population, TC. BUT, 5.7% of the really sick influenza patients had a gene variant extremely rare in screenings of the general population (0.3%)– a CC.
Changing that TT to a CC, theoretically, leads to alternative RNA splicing, which leads to a alternative IFITM3 protein that is 21 amino acids shorter. If its shorter, it might not work well (or at all), leading to humans that get really sick from relatively benign influenza variants– like what we saw in the mice that lacked the IFITM3 gene. Maybe this is why some people got REALLY SICK from Swine Flu, but most people didnt even notice they were infected at all.
Well, you cant very well get a bunch of IFITM3-CC mutants in the lab to perform experiments on them to test this hypothesis. So these scientists generated a variant of IFITM3 that lacked the first 21 amino acids, like they think is happening in IFITM3-CC people. They then expressed it, IFITM3, or nothing in cells they infected with influenza. The shorter IFITM3 was only slightly better than nothing at restricting influenza replication, while the full length IFITM3 did just fine, implying that people with the IFITM3-CC mutation would, in fact, have a harder time controlling influenza infection.
Of course, this paper doesnt explain the other 94.3% of patients admitted to the hospital for Swine Flu infection with normal IFITM3, but its still pretty cool– It tells me that when genomic screens become cheap/widely available, we need to find the 0.3% of the population that is a IFITM3-CC mutant, and make damn sure they are first in line to get all of their immunizations.