VIRUS

Should we be afraid?

Hens’ eggs being inoculated with the avian influenza virus. Research conducted in one of the Centers for Disease Control and Prevention (CDC) laboratories in the USA. © Greg Knobloch
Hens’ eggs being inoculated with the avian influenza virus. Research conducted in one of the Centers for Disease Control and Prevention (CDC) laboratories in the USA. © Greg Knobloch
Head of the yellow fever mosquito (Aedes aegypti). Colourised image. © Institut Pasteur
Head of the yellow fever mosquito (Aedes aegypti). Colourised image. © Institut Pasteur
Type A influenza viruses are the only ones that can cause natural infections in wildfowl, especially the sheldrake (Anas tadorna). Numerous antigenic subtypes exist that are defined on the basis of two membrane glycoproteins of Type A influenza viruses (haemagglutinin, ‘H’, and neuraminidase, ‘N’). These two groups determine the virulence of the infection: either the mortality rate is close to 100% (mainly from subtypes H5 and H7) or the infection is mild and of a respiratory nature. Since early 2003, there have been a number of epizootics involving humans: H5N1, H7N7 and H7N3. © Institut Pasteur
Type A influenza viruses are the only ones that can cause natural infections in wildfowl, especially the sheldrake (Anas tadorna). Numerous antigenic subtypes exist that are defined on the basis of two membrane glycoproteins of Type A influenza viruses (haemagglutinin, ‘H’, and neuraminidase, ‘N’). These two groups determine the virulence of the infection: either the mortality rate is close to 100% (mainly from subtypes H5 and H7) or the infection is mild and of a respiratory nature. Since early 2003, there have been a number of epizootics involving humans: H5N1, H7N7 and H7N3. © Institut Pasteur

Warning signs of new worldwide viral epidemicsare sounding alarm bells among scientificcommunities and the media: we saw SARS in2003, Chikungunya in 2006 and H5N1 avianinfluenza since 1997 - not to mention theterrible outbreaks of Lassa, Ebola and West Nilehaemorrhagic fever viruses. These epidemics areour society's sword of Damocles; and are onlyavoidable through a drastic research increase.

‘The world is teetering on the edge of a pandemic that could kill a large fraction of the human population' was the title of an article by virologist Robert Webster, published by American Scientist in March 2003. Written in the midst of a severe acute respiratory syndrome (SARS) epidemic, the highly controversial article conjured up a disaster scenario where a deadly new virus would render doctors and public authorities powerless. Although this worst-case scenario has receded, it is a statistical probability that a viral pandemic lurks around the corner. The latest World Health Organization (WHO) report points the finger at 11 virus types of the 18 infectious diseases that emerged or reemerged between 1996 and 2004, including the yellow fever, SARS, West Nile and Ebola viruses. The outlook is disquieting, and the most serious threat is the infamous H5N1 influenza virus, which is highly pathogenic among birds and "since 2003 has been responsible for the greatest avian panzootic the world has ever known," says doctor and bio statistician Antoine Flahault, who helped WHO develop its Global Influenza Surveillance Network (FluNet).

Although the ultimate aim of scientific research into viral diseases is of course to find human vaccines - as happened with smallpox, which was eradicated in 1979 - first and foremost it is necessary to understand the highly complex mechanisms of viruses, upstream of vaccine development. Viruses are ‘simple' sequences of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) surrounded by proteins, and are not themselves living organisms. They are obligate parasites that need to infect other organisms to replicate. It is a constraint that also offers them unlimited opportunities: it was a new coronavirus, a hitherto unknown cousin of the common cold virus that gave rise to the Asian SARS epidemic in 2003. Following the crisis of acquired immune deficiency syndrome (AIDS), which stemmed from an adaptation of simian immunodeficiency virus (SIV) to humans, it seems that SARS was also transmitted by animals.

Will the species barrier be strong enough to contain the spread of H5N1, whose natural reservoir is birds? Pierre Roques, from the Institut des Maladies Emergentes et Thérapies Innovantes (FR), takes a guarded view: "Faith in the species barrier has been shaken. Even though swine fever, which kills pigs very rapidly, never infects their human contacts, swine influenza is perfectly capable of crossing the species barrier. In fact, one of the mechanisms thought to be responsible for the new variants of human influenza is a recombination of bird viruses that infect pigs and are then passed from pigs to humans. Influenza is more organ-dependent than species-dependent, as the virus can cross the species barrier between warm-blooded animals with similar organs. The H5N1 virus, which is optimal at 39°C, has still not adapted to humans, who have a body temperature 2 to 3 degrees lower than that of birds." From a molecular standpoint, whether or not humans contract influenza depends on the haemagglutinin (H) number used to classify the different influenza A viruses.

We know of 16 variants, only three of which are fully adapted to humans and infect us with our familiar seasonal influenzas.

Haemagglutinin is the key which the virus uses to enter its host's cells. Antoine Flahault says: "According to our present knowledge, only the H1, H2 and H3 viruses have caused pandemics in the entire history of humankind.

Even though events formerly thought to be impossible have in fact become possible today, the species barrier against influenza viruses is extremely robust. These viruses have been circulating for a very long time.

Despite the close proximity in which birds, poultry and humans live in some countries of the world, there is no record of an epidemic outbreak of H5N1 in humans occurring in the 20th century, although there were several episodes of avian influenza." According to some scientists, however, it would take only one element in the H5 structure to change to remove the avian specificity of H5N1 viruses. Humanisation of the virus, which could occur by the recombination of H5N1 with other strains, would then open the door to a pandemic. Of all the humans who contracted the virus (in most cases following direct contact with wildfowl or infected poultry), 60 % died. What is the worst case imaginable?

That the world is struck by another pandemic on the scale of the 1918 one, which claimed between 20 and 40 million lives. The 1918 virus was a new strain (which we now know to be H1N1) with which humans may never have previously come into contact. "The main difference between seasonal and pandemic influenza is that only a fraction of the population is susceptible to seasonal influenza because of acquired immunity. By contrast, the entire population is susceptible to a strain that is new to the human race. Some sufferers with few symptoms are bound to escape detection and go on to infect others who may be severely affected themselves," explains Antoine Flahault. It also depends on the virulence of the attack: the aggressiveness of the Ebola virus, which killed 50-90 % of those infected in just one to two weeks, actually makes it easier to contain.

A virus is a ruthless coloniser that hijacks the inner workings of living cells for its own ends. It uses the cell's own fatty acids, amino acids and nucleic acids to multiply, then moves on once it has exhausted the cell's reserves. Cunningly adapted to its host, some viruses infect a single cell type. For instance, the human immunodeficiency virus (HIV) targets only CD4+ T lymphocytes. And if RNA polymerase, the protein that viruses use to replicate themselves, makes errors of replication, viruses simply exploit this advantage to evolve their genome! In 2006 in the Indian Ocean the Asian tiger mosquito (Aedes albopictus), a cousin of the yellow fever mosquito (Aedes aegypti), which is the traditional Chikungunya vector, became a super-vector following an adaptive mutation of the virus.

This was later demonstrated by Institut Pasteur by comparing different viral strains. The Asian tiger mosquito is much more effective at infecting humans than its cousin the yellow fever mosquito because it produces 100 to 1 000 times more virus.

That being said, it is not so easy to adapt to an entirely new environment, even for a virus. "It takes hundreds if thousands of years for host-virus coevolution to allow infection of the host and viral agent," explains Antoine Flahault. "There are hundreds of different mosquito varieties that do not permit virus transmission. Although AIDS has adapted to humans and other primates, it still has no capacity to act as an arbovirus (short for an arthropod-borne virus) that could infect a mosquito, develop in its intestine, migrate to its salivary glands and reinfect humans after replicating." Viruses are locked in a battle for supremacy over an entire ecosystem. The species chain concerned by avian influenza includes natural reservoirs: more than 60 species of wildfowl, ducks, swans and flamingos are traditional healthy carriers of the avian influenza virus - and all are animals that know no borders. The list also includes domestic poultry, which can become vectors of disease to the humans trading them. Economic and social conditions, in this case the poultry food industry, also play a part in the emergence of epidemics. It might be useful to extrapolate from the 1918 pandemic. "In 1918, between 80 and 85% of deaths arose from bacterial complications. Infected people died en masse from pneumonia, whereas nowadays they would be given antibiotics," explains Antoine Flahault. This means that to guard against an influenza pandemic it would be necessary to stockpile not vaccines but antibiotics. What is certain is that the war against the next viral pandemic will be fought by an elite army of entomologists, veterinarians, epidemiologists, virologists and immunologists, as well as clinicians, sociologists, economists, modellers and manufacturers of pharmaceuticals and medical appliances.

WHO, which has the task of envisioning a future attack and defining ways to prepare for it, is convinced that our primary foe will be H5N1. Let's hope that the threat will come from a predicted direction for once.

Axel Meunier



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