on flu pandemics
a briefing document
life and amibitions of a virus
on flu pandemics
During the last few weeks, I have become interested in viruses and the immune system. Be warned that I am no expert [see linked article and reference below], but I find it all very fascinating, and thought this latest flu scare an interesting opportunity to write a little on the subject. As usual, I shall probably develop this as the notion takes me.
A successful bug has several problems to solve, if it is to have a long and happy life, and to leave many descendants to carry on its dynasty and good works. What a good virus does not do is kill you outright, it doesn’t even want to send you to bed. It wants you out there, spreading its babies. Viruses are not out to get you, they just cause their annoyance by getting on with their normal lives, eating cabbage with a side order of braised human. It is very inconvenient for the virus if you die, thus influenza has far more descendants running around the planet than ebola.
Viruses tend to specialise in terms of which part of you they fancy. Some go for the mouth-faecal route, some go from generation to generation through birth and mother’s milk, while others are rather keen on sex and snogging. The flu virus is a brilliant piece of engineering and chooses your breathing apparatus.
As you will notice, flu normally only kills those with an immature immune system or those over 65 with an immune system that is wearing out. In the USA, 80% of deaths from influenza are normally amongst those over 65. Most deaths are caused by secondary infections, particularly pneumonia. What is strange about the 1918 second wave was that it killed a large percentage in the 20-40 year old age group. This is still not understood. One theory is a violent reaction by the immune system [for those interested, look up cytokine storm] among those at the peak ability of their immune system - a great deal of the misery that you feel from a flu attack is your immune system fighting the invader. Another possibility is a large number of young men crowded together in unhealthy conditions at the end of the war.
Influenza is what Sompayrac calls a hit-and-run virus. It dives into your body does its thing, mutates rapidly and then your immune system kills it off. Influenza is spread by the extremely efficient route of droplet infection by coughs and sneezes. It then continues to mutate and, in a year or two, or three or four, it’s back again for another trip in a form sufficiently mutated that your body takes a while to recognise and smack it down again, by cranking up the adaptive immune system memory to send the virus again on its travels.
The numbers of cases are far too low at present to give a clear idea whether this latest outbreak is a serious threat, or just another passing bus. the bug is obviously acting very differently in Mexico than elsewhere.
The common cold is often confused with influenza, but is a very different animal. The common cold (rhinovirus) is normally seen off by your innate immune system within a week of invasion. The adaptive immune system is never activated. Consequently, you don’t gain immunity to the common cold so it is regularly back for another round of fun. This virus tends to infect Westerners, on average, once a year.
Both the flu virus and the rhinovirus seek out your airways, but in very different areas. Both these viruses can’t tolerate the acids and enzymes in your digestive system. Consequently, evolution has provided you with a marvellous traffic system. Cilia in the upper respiratory tract brush detritus downwards towards the throat; whereas below that level, cilia run an up escalator towards the throat. At which point, you either swallow the rubbish into an acid bath or spit it out, we hope, into a tissue and not on the street!
The rhinovirus doesn’t like your body temperature, so prefers your upper airways, in your head, where the temperature is about 91°F/32.8°C. The flu virus prefers body temperature (98.6°F/37°C). So the rhinovirus will not raise your temperature, and the old wives’ saw of keeping warm to “not catch your death of cold” has some merit. The common cold will just make you feel ‘rotten’; flu is likely to make you feel doubleplusungood rotten, aching muscles, aching bones, which drives all sane people to bed for four or five days. Notice, even here your own genes knows what’s best for you and for everyone else. In bed, your system isn’t wasting time and energy running marathons, but is working overtime to kill the foreign army. Nor is it so easy for the critters to spread around.
Both these viruses can leave you open to secondary, usually bacterial, uninvited guests, and they will normally raise your temperature; or even turn a nuisance into a danger. But yet again, the dangers are far greater with flu.
Various viruses use DNA, RNA or negative RNA to carry their genetic data. The flu virus uses eight strands of negative RNA. The polymerase used to copy the RNA is subject to making many errors. This is much to the advantage of the virus as it tries to outwit immune systems. The virus changes in two main ways.
The first is called antigenic drift. Occasional mistakes are made in copying the RNA. Thus the long strings of RNA gradually vary, first by one place, then by another at random.
Now most human cells display short strands of the various chemicals found within the cell, on the outside of the cell on specialised ‘billboards’ [MHC molecules]. If your immune system has previous experience and recognises one of these strings as enemy action, war against the invading virus will rapidly crank up.
But if the sequences have been sufficiently changed that the small strands are not recognised, the flu virus gets a head start and you’re off sick for several days until the adaptive system gets its full armament factories going, and other methods of attack.
The innate immune system starts to realise that something is wrong when cells start pumping out cytokine [messenger] interferon and cells start dying. This gradually winds up the adaptive immune system over a period of about a week.
The second nasty trick is called antigenic shift. This happens when the virus manages to swap a complete RNA strand. This happens when two sustantially different variants of the virus get into the same host. Thus an example is when an avian RNA strand replaces its equivalent strand in a human flu virus while both are inside a pig. When this shift happens, it becomes particularly difficult to predict what delightful surprises the new virus may have in store.
Thus you may hear references to H1N1 flu, H5N1 flu etc., referring to the two first strands listed above. These are the genes expressed on the surface of the virus, and are, thus, most relevant to immune system response.
The following is taken from an excellent and clear discussion [5-page .pdf] of flu virus resistance through mutation, relative to Tamiflu (Oseltamivir)
From the World Health Organization, A revision of the system of nomenclature for influenza viruses, WHO Memorandum Bulletin 58 (1980) 585–591:
For images of a model of part of the 1918 flu virus, and access to other virus model images.
Developing a vaccine specific to a particular form of ‘the flu virus’ will take about six months. First, the virus has to be sequenced/analysed.
The immune system seeks markers on the surface of the virus, and then sets about destroying it. The flu virus is a rapid mutator. It swaps about the markers. Some of those markers your body will probably have seen before if you are (say) middle-aged. An experienced immune system may start cranking up earlier, and repel the boarders before they get a grip. Vaccinations will also show the immune system some flu markers.
Each year, the vaccination made available is tailored for the variants forecast to be due that year.
The 2008/2009 vaccine usually contains the following three strains:
It is expected that this will also be appropriate for the 2009/2010 vaccination. The swine flu variation, also a H1N1 A-type variant, is being dealt with by a separate new vaccination at the moment.
Tamiflu is a neuraminidase inhibitor! Here’s some of how it works.
Tamiflu and Relenza are sialic acid mimics to which the neuraminidase binds much more tightly than to real sialic acid. Neuraminidase is produced by the flu virus while it is working to escape the cell (the one it has infected). Getting out of the cell is a problem for flu viruses. The virus has to shave the sialic acid to escape the cell. The virus, instead of shaving real sialic acid to escape, winds up shaving the sialic acid mimic, Tamiflu or Relenza. If it didn’t shave off the sialic acid, the flu virus would get sort of glued to the infected cell.
By the time the viruses are out of the cell, Tamiflu is too late. Thus the 40-hour time limit for its use.
As with vaccinations and acquired immunity, the flu virus is capable of mutating to head off these antivirals.
Summary from three recent studies.
There are two main strains of flu virus, named A and B. A includes the H1N1 strain. Meanwhile, flu mutates like billyo in normal circumstances.
The present main concerns are with the recent H1N1 strain (‘swine flu’) and Tamiflu.
Once it is decided which strain of flu virus is being discussed, then suitable treatments can be suggested, but as the window is longer than testing times and there are several variants around at any one time, it is a matter of guesswork which vaccinations or anti-virals are relevant.
Tamiflu is a neuraminidase inhibitor. There are two of these so far FDA approved, with trade names Tamiflu and Relenza. There are two other treatments used for flu called adamantanes, they are Amantadine and Rimantadine. These latter two are not deemed useful for B viruses (H1N1 is an A virus), and the H3N2 virus currently circulating is resistant to them.
As you will have noticed, there was an H1N1 virus around last year that was resistant to Tamiflu, while the present H1N1 (‘swine flu’) resistance has not been found - yet. The ‘N’ molecule (neuroamidase) is made up of about 467/8 amino acids. Now these complex (neuroamidase) molecules fold predictably according the amino acid sequence. Keeping in mind that the flu virus relies on rapid mutation, certain random changes in the amino acid sequence can result in the Tamiflu molecule not fitting tightly enough, or as accurately, and thus may fail to block/disrupt the neuroamidase action of the virus. This is approximately how resistance to a substance like Tamiflu develops.
Of course, a change in the neuroamidase may also make the virus ineffective - typical evolution in action. Meanwhile, the biochemists are understanding the little beggar ever better and are working on improving the inhibitor molecules and on developing new attacks on the virus.
These drugs are fall-backs if vaccination does not work, or if the current flu version gets a start. (It takes about six months to obtain a useful vaccine.) Each year, the medical warriors are trying to keep ahead or get ahead of flu, but flu is a very crafty and agile monster.
This article should also have mentioned other variables such as population density (how manny people are available for infection per square metre), and how quickly an infection kills a host.
Successful infections are generally careful not to kill hosts. The 'best' ones mutate fast so they can have another go, for example flu and the common cold. Successful infections also try to keep their hosts alive and infectious for as long as possible, as with syphilis and HIV-AIDS.
The critical reproduction number is 1. Above 1, the disease steadily expands; below 1, it steadily dies out.
email abelard at abelard.org
© abelard, 2009,28 april
the address for this document is http://www.abelard.org/briefings/flu_influenza_pandemics.php