Down With the Sickness,
or why you should be glad to have the flu now (as opposed to later)
Being sick is no fun. Congestion, fever, coughing – there’s nothing good about it. Or is there? For a single human being the answer may be "no" but for large groups of humans the grim reality of a multi-stage pandemic makes beating the rush a smart strategy.
First let’s talk about the adaptive immune system. Every time your body encounters a foreign protein such as a virus, your immune system kicks in and starts the process of identifying the invader, teaching other cells how to recognize it, and systematically degrading the virus wherever it is found in the body. There are many different cells involved in this process but the big players are the special white blood cells known as T-cells, B-cells, and macrophages. Just a few words about each will be sufficient for our later discussion.
T-cells mature in the thymus (hence "T") and are responsible for several important immune activities: secretion of cytokines (small chemical triggers that turn on various parts of the immune system), destruction of infected cells, and eventual suppression of immune response (if your immune system doesn't know when to turn off it eventually attacks itself). B-cells are maintained in the bone marrow (hence "B") and work by engulfing an invader, chewing it up and displaying bits and pieces of it on the cell surface. T-cells that are already on alert for the same invader bind to the B-cell and secrete cytokines telling the B-cell to multiply and mature, after which it churns out antibodies that bind to the invader and signal its destruction. B-cells that survive this process through multiple rounds are called memory B-cells and are the repository of much of humans’ adaptive immune repertoire. Finally, macrophages ("big eaters") literally swallow viral particles and even whole bacteria, digesting them and displaying bits and pieces of them in much the same way that B-cells do, eventually recruiting T-cells to flag the invader and make it easier to find and consume. A single macrophage can consume a hundred bacteria before its own digestive enzymes break it down from the inside.
Now that we now a bit more about the major players of the immune system, let’s talk about one particular invader: the influenza virus. A virus is a small bundle of proteins that can be thought of as a kind of microscopic mosquito, with long "legs" that latch onto a target cell and a dense "body" containing its own genes for making more copies of itself.
The influenza virus is a rough sphere or filament coated with proteins that bind to human cells using a protein called hemagglutinin (abbreviated HA) that works by binding to a particular sugar modification called sialic acid. Once bound, the cell "ingests" the virus in a special bubble called an endosome, the purpose of which is to isolate the virus and fuse the endosome with an acidic lysozome in order to degrade the virus down to harmless nuts and bolts. HA is specifically adapted to this use strategy against the cell, however; the acidic environment causes it to alter its shape and helps the virus escape the lysozome, where its RNA genes can be released directly into the cell and the copying process can begin. Once this happens, the cell cannot tell which RNA is viral and which is its own, so its cellular machinery begins turning viral RNA into protein – new copies of the virus – and the battle is effectively over for that cell.
The other major player for the influenza virus is called neuraminidase (NA), an enzyme that is critical for release of the many-times-copied virus out of the cell. The HA part of these copied viruses would like nothing better than to bind to the sialic acid in the cell wall once again, just as it did when entering the cell; in order to prevent that, NA cleaves the sialic acid off of sugar molecules in the cell membrane and helps the viral copies escape the cell and spread out to look for new cells to infect. Some of the most potent anti-influenza drugs currently available, including TamiFlu, specifically inhibit viral neuraminidase, a perfect target because humans do not possess that enzyme.
Because these two enzymes (hemagglutinin and neuraminidase) are so critical for the activity and pathogenicity of the influenza virus, virologists classify strains of influenza based on which versions of those two enzymes characterize that strain. There are 16 types of HA and 9 types of NA, meaning that there is a range of 144 individual influenza strains in this group. Strains of related pairings of these two enzymes compose the major classifications of the flu virus, such as the avian flu that was the specter of the 1990’s (H5N1) as well as the current strain of interest: H1N1 swine flu.
H1N1 is a subtype of the Influenza A class, and is composed of eight single-stranded RNA molecules that code for eight individual proteins. Unlike many viruses, however, these eight genes are not all part of a single long string of nucleic acid; and because they are physically separate, they lend themselves well to a process called reassortment in which a cell infected by different strains of the influenza virus will package genes from different viruses together into a new, hybrid virus. By analogy, imagine the cell as a car manufacturing plant: viral proteins are assembled into cars (viruses), all of which look pretty similar. The owner’s manual (RNA genes) that goes into each car, however, might be made up of pages taken from two different models (viral strains), so when a particular car (virus) later infects a new cell, the hybrid owner's manual it comes with gives rise to an entirely new model of car (virus). Reassortment is what allows influenza viruses from different species to commingle and generate new, more pathogenic hybrid strains of the virus, as well as helping them continue to elude the best efforts of the immune system to recognize and eradicate the virus. It also makes it difficult for scientists to predict which strain of influenza should be included in this year's flu shot. The current H1N1 model is what is known as a triple reassortment - a virus carrying genes from avian, swine and human influenza strains.
So what about the H1N1 model? Scientists are concerned about the current outbreak of H1N1 that began in
So far the North American H1N1 shows no signs of being capable of creating a cytokine storm effect in its victims. So we’re home free, right? As it turns out, it’s not that simple. Researchers who have charted the progression of the 1918 epidemic show a peculiar three-stage pattern in which the H1N1 strain killed 5 people per thousand in July of 1918, then 25 per thousand in November of that year, and finally 12 per thousand in March 1919. The current scientific explanation of this pattern, based on viral RNA extracted from well-preserved victims who died at different stages of the epidemic, is that there was a critical mutation of the strain in just four brief months between the first and second emergence of the H1N1 virus. Normally when a virus gains in strength its victims are more likely to stay home and not spread it, but in late 1918 World War I was still raging, and it is theorized that the concentration of military personnel around the world fostered the spread of the more pathogenic mutant. Because the mutant was so lethal, it actually inhibited its own reproduction and thus the third emergence showed another new mutant, this one less pathogenic. By that time the war was over and sociological pressures that favored the spread of the virus were far reduced; there was no fourth emergence.
So what does this teach us regarding the current H1N1 outbreak? Quite a bit, actually. Our world today is much different than the world of 1918. Air travel can now spread a virus around the world literally overnight, exposing vast numbers of people in a far shorter span than was ever true in the crowded field hospitals and trenches of World War I. The speed at which a pandemic could take hold in many major cities around the world means the window for an effective response time is also much shorter. On the other hand, we now know about cytokine storms and how to prevent them using a variety of drugs like corticosteroids, free radical scavengers and TNF-alpha inhibitors. Further, powerful drugs like TamiFlu provide an effective answer to pandemics, especially among healthcare professionals who are on the front lines in any major public health threat. And most reassuringly of all, epidemiologists are well aware of the possibility of pandemic and are, if anything, overeager in their efforts to spread the word about that possibility. This may create some annoying overdramatization in the media, but considering that electronic media now encircle the globe far faster even than air travel, any increase in public awareness remains the first, best line of defense against a pandemic outbreak.
And one more thing about the 1918 H1N1 pandemic: those who caught the earliest, least pathogenic strain of the virus were largely immune to later mutants. So if you’re a parent thinking about keeping your child out of school, or if the guy next to you at work keeps coughing in your direction, just remember that if things go bad, you’re probably better off catching that flu now when it’s in the mildest form – just in case.
For more information:
http://www.newscientist.com/article/dn17072-first-genetic-analysis-of-swine-flu-reveals-potency.html
http://www.newscientist.com/article/dn17077-flu-outbreak-the-pig-connection.html
http://www.cnn.com/video/?/video/health/2009/04/28/am.gupta.swine.flu.model.cnn
© AQOS, Peter Smalley (2009)
Distribution with attribution is appreciation
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