Not to be sneezed at

7 February 2012

 Influenza virus
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Influenza virus by Sanofi Pasteur, on Flickr

With the flu season upon us, at the first Packed Lunch talk of 2012 in Wellcome Collection, Professor Wendy Barclay – Chair of Influenza Virology at Imperial College – discussed her current research. Penny Bailey was there to hear about the race against a constantly changing virus.

We think of flu as a human disease, but its main hosts are birds (particularly wild waterfowl), with whom the virus enjoys a very successful relationship. It causes few symptoms in birds and passes easily from one host to the next, courtesy of the waterholes where large flocks of migratory birds gather to defecate and drink. Infected birds shed the virus in their gut into the water, which others then imbibe.

Occasionally the virus crosses to pigs and chickens on nearby farms. From pigs it can pass to humans – not through pork products, but through contact with the live animals. It can also pass directly from birds to humans, as the H5N1 virus did in Southeast Asia in 2007. This ability to move around in lots of different ways is crucial both to its ‘success’ and to the threat it poses to people.

Influenza’s new clothes

Like many viruses, the flu’s genetic material is made of RNA. RNA is much more mutable than the DNA in our human chromosomes, the extreme stability of which restricts our evolution to a leisurely pace over millennia. The flu virus, by contrast, swaps bits of RNA around to change its coat of surface proteins within months – that rapid evolution allowing it to elude the host’s immune system, and any new vaccines aimed against it.

The flu virus is too small to see without an electron microscope, but Wendy brought along a model – a sparkly, remarkably symmetrical ball with spikes sticking out of it – to demonstrate how it changes its protein coat. The spikes (or surface proteins, or ‘antigens’) are shaped like lollipops, each comprising a head on a stalk that sticks out of the body of the virus. Our immune systems detect these antigens and generate specific antibodies against them that target the virus for destruction.

The flu virus ‘wears’ two main types of spike or antigen, labelled ‘H’ and ‘N’. Each of these has a number of subtypes: there are 16 known ‘H’ antigens (H1 to H16) and nine ‘N’ antigens (N1 to N9). Combining the two gives the names of particular strains of the virus, such as H1N1 (the strain responsible for the 2009 swine flu and 1918 Spanish flu pandemics), H5N1 (the 2007 avian flu pandemic) and so on.

The numerous possible combinations of ‘H’ and ‘N’ – plus the fact that an antibody against any one subset of either won’t protect against another subset – pose a challenge for vaccine makers, who have to design a new vaccine each year to target the most prevalent strains circulating.

The dream is to develop a once-only, one-size-fits-all vaccine that will protect us from all possible strains of the virus. In a bid to realize it, researchers are attempting to design a vaccine that will target the stalks, rather than the heads, of the lollipop-shaped antigens because these are structurally similar across all different types of H and N antigens. At present our immune systems don’t readily make this type of antibody, so it’s a question of finding a way of persuading them to do so.

Until we can do that, our bodies will be constantly running to keep up with the flu virus’s rapidly changing genome and ‘coats’.

Altruism and silence

It’s not a battle to the death. In fact, Wendy points out that it’s in the interest of the virus not to kill its host. If it only makes 100 copies of itself, that’s still enough to pass on to a new host. A million copies would overwhelm our bodies and kill us (as probably happened in the 1918 flu pandemic), effectively making the virus ‘homeless’. The most successful viruses are ‘silent’ and cause few symptoms in the host, like those living in wild waterfowl or the numerous viruses all of us humans harbour but are unaware of because they don’t make us ill – the herpes virus, for example.

Our bodies compromise in turn. When we catch a flu virus, some of our cells die an ‘altruistic’ death, to protect the rest of the cells in our bodies by limiting the number of copies the virus can make of itself.

We also have to keep a balance between by releasing inflammatory chemicals (such as cytokines and chemokines), which push up our temperature and destroy the virus, and damaging our own tissues with those same chemicals: a ‘cytokine storm’ can be fatal. The jury is still out on whether we should take paracetamol to lower our temperature during flu or let it take its course.

The 2009/2010 H1N1 swine flu turned out to be far more harmless than we first feared, and most people infected didn’t even notice they had it – but it did kill some people. Wendy believes the different impact of the virus on different people may be due to subtle changes in our genomes that protect some of us from infection (like mice, nearly all of whom have a gene that prevents them getting flu).

Alternatively, some people who got off lightly may only have received by a low dose of the virus that their body could deal with efficiently, generating antibodies against it (the basis of vaccination). Or they may have better innate barriers to infection, such as mucus and cilia. They may even have been First Defense users. Apparently it does work – Wendy confessed to using it herself on occasion. It’s very acidic (and viruses are sensitive to low pH), so it kills them in our nose and throat when they first infects us. But, she warned, we would have to ‘sniff a lot’ for continuous protection.

Ferret flu

Since mice have a protective gene that rules them out as models for human flu, the ferret is the gold standard model for laboratory studies. Ferrets and humans have the same molecules on their respiratory tract that allow the virus to stick to and invade the cells there. And ‘ferret flu’ follows the same course as human flu: two to three days of fever, 12–24 hours after infection, followed by coughing and sneezing two or three days later (the virus denudes the protective layer of mucus and cilia in our respiratory tract).

Wendy used a ferret flu model during the 2009/2010 swine flu pandemic to try and answer a question numerous journalists were phoning her to ask: at what stage of the illness were people most infectious? And when could they return to work without risk of infecting their colleagues?

One ferret (the ‘patient’) received a dose of flu on a known day and then had two ferret ‘visitors’ – one on the first day before the infected ferret was symptomatic, and one on day five when fever had abated and the animal was coughing and sneezing. Unexpectedly, the first ‘visitor’ developed a worse case of flu, pointing to the unfortunate conclusion that we’re most infectious when we don’t even know we have the flu yet.

Genetically engineered flu

Wendy also gave her opinion on the controversial study published in November 2011 showing that five tweaks to H5N1 (that has killed 500 people) make it more contagious. She believes the scientists were trying to answer a very vital question – how likely is H5N1 to jump from birds to humans, or to another species? – by anticipating the mutations the virus would need to jump from birds to ferrets, then ferret to ferret.

We spend vast amounts of money globally stockpiling vaccines and drawing up plans to protect people from a possible H5N1 pandemic. But there are 16 (or more) types of bird flu virus – any one of which could mutate and jump species to humans. If the research showed that H5N1 would never pass to humans, we might want to change our priorities and look at other strains.

The researchers also used the genetically engineered virus to look at whether the drugs and vaccines we’ve developed against H5N1 actually work – something that hasn’t yet been tested on a real human virus.

Living on the edge

We talk about the behaviour of the flu virus, its ‘success’ and its ‘relationship’ with its host. Does this mean it is actually alive? Wendy’s take on that (still hotly debated) question is ‘almost’. The flu virus is, she believes, on the brink of life.

Finally, how worried should we really be about a possible global flu pandemic? That it will happen is a certainty, she says. There are so many viruses in the wild, in pigs and birds, more of which will definitely emerge and jump to humans, and overcrowded populations of people offer perfect conditions for a new strain to take off and spread rapidly. On a brighter note, however, not all strains will be deadly.

Penny Bailey is a writer at the Wellcome Trust.