ON 5 JULY this year the SARS epidemic was officially declared over. Doctors breathed a sigh of relief, but for scientists the work was just beginning. In dozens of labs all over the world, research on the virus is intensifying.
The researchers aren’t just worried that SARS might make a comeback – although that is still a real possibility. They are concerned because it seems to have killed people by triggering a runaway release of inflammatory chemicals called cytokines, in a so-called “cytokine storm” that can be more deadly than the virus itself. This is how numerous diseases kill, from pneumonia to flu, making it one of the hottest topics in infectious disease research right now. And it has proved maddeningly hard to treat, with average fatality rates topping 50 per cent in full-blown “septic shock”, as the clinical condition is known.
SARS, a coronavirus that came from nowhere to kill around 1 in 6 of its victims, has added an urgent impetus to the research. There’s reason to believe that any new infectious disease that crosses from animals to humans could trigger this reaction. “A lot of people are clued into this as a very important way of understanding viruses,” says virologist Wendy Barclay at the University of Reading, UK. “It’s an up-and-coming subject.”
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The immune system isn’t supposed to harm us. It evolved mainly to defend us against invading pathogens. It comprises an army of different cell types in the blood and the body’s other tissues. As well as the more well-known molecular weapon of antibodies, the immune system deploys a mind-boggling array of chemical messengers called cytokines. There are at least 18 of a type called interleukins, three main groups of interferons, tumour necrosis factor alpha (TNF-α), and many others. In the past few years, as new molecular techniques have come online, it has become clear that these messengers turn on hundreds of genes in different cells, unleashing a fiendishly complex cascade of effects. Some cytokines act locally, killing nearby cells that could be infected with virus, partly by turning on cell suicide pathways. They also recruit more immune cells to the area, partly by increasing local blood flow, resulting in inflammation. Some cytokines have systemic effects, making us feverish or lethargic.
When SARS surfaced this year, doctors observed that in fatal cases the patient’s condition tended to suddenly worsen in the second or third week. A team led by Malik Peiris, a virologist at the University of Hong Kong who was the first to isolate the SARS virus, showed that this happened despite the virus having largely been cleared from the body. Together with the type of lung inflammation they saw – and the fact that older people were more likely to die – this matched a pattern in other infections known to be caused by cytokine levels getting so high that healthy lung cells died too. “Once you trigger some of these pathological processes, they take on a life of their own,” Peiris told 91av. “It’s a complex network full of positive and negative feedback loops and it can spin out of control.”
It reminded Peiris of another potentially lethal infection: flu. This virus rarely kills healthy adults, but every so often a new strain emerges to which even the strongest succumb. In the 20th century, new strains wreaked devastation around the world on three occasions, and most virologists consider it to be only a matter of time until the next lethal pandemic. Scientists would love to know what makes these strains so deadly. Recent research suggests it is because these are the ones most likely to whip up a cytokine storm.
The bird flu that jumped to 18 people in Hong Kong in 1997 and killed a third of them was probably our most recent pandemic near miss. Robert Webster’s team at St Jude Children’s Research Hospital in Memphis, Tennessee, showed last year that one gene from this virus made it impervious to two key cytokines that normally kill virus-infected cells, gamma-interferon and TNF-α.
Peiris’s team showed a few months later that this flu strain also gave a powerful boost to TNF-αproduction by human immune cells (The Lancet, vol 360, p 1831). The combination of cytokine release and resistance is a recipe for a runaway immune response, he concluded.
Something similar may have been going on with the deadliest known flu strain in history, which killed an estimated 40 million people worldwide in the pandemic of 1918. Jeffery Taubenberger of the Armed Forces Institute of Pathology in Washington DC has partially reconstructed the virus and investigated its effects on cultured cells. He has shown that it could suppress many human genes that are normally switched on by interferon – another case of cytokine resistance.
Wendy Barclay says SARS and killer flu could have similar effects in humans because they have both only recently jumped from animals to humans. Viruses that have circulated for a long time in humans have come to terms with our cytokine system, she says, in ways that allow the virus to multiply without killing us. To spread, the virus needs us alive. “But new viruses haven’t learned that yet,” she says. That suggests the next new disease to cross to humans might also unleash a cytokine storm – making whatever we can learn about our response to SARS that much more valuable
So what are the prospects for preventing or treating such diseases? Doctors dealing with SARS turned to corticosteroids, hormones that suppress the immune response, including cytokine release. Although there were no controlled clinical trials of this approach, it helped in many cases. But corticosteroids are a blunt instrument, shutting down a whole array of immune responses. Other researchers wondered if it might be better to block specific cytokines. TNF-α is known to play a key role in septic shock, and there’s evidence to suggest it was important in SARS, too. In their analysis of lung tissue from patients who died from SARS, Peiris’s team found macrophages that had been eating red blood cells – a taste known to be induced by TNF-α. Another cytokine that has this effect is macrophage inhibitory factor (MIF). Kar Neng Lai’s team at the University of Hong Kong found high levels of this cytokine in SARS patients and, tellingly, more so in patients with worse lung damage.
By sheer coincidence, in February, days before SARS hit Hong Kong, Lai’s team had shown that antibodies to TNF-α or MIF helped prevent lung damage in an animal model of inflammatory lung damage. Anti-TNF-α is already used as a drug for autoimmune conditions such as rheumatoid arthritis, so Lai got permission to carry out a human trial with it in severe SARS cases in Hong Kong. As the research has not yet been published he will not reveal the results, beyond saying that the patients’ responses were “not totally satisfactory”. But he points out that the dose used was the same as that for arthritis, which may be too low for SARS lungs. “We will consider a higher dose in future,” says Lai.
Other scientists are using cultured cells to study whether the virus induces or resists TNF-α, MIF and other cytokines. But so far they are keeping tight-lipped about their findings. “No one wants to talk about results yet,” says Albert Osterhaus of the University of Rotterdam, who helped prove that the SARS virus causes the disease. When they do, there are a lot of drug companies and doctors who will be listening.
There is a potential downside to this approach, though. If we suppress the very cytokines that defend us, might we give the virus free reign to multiply out of control? Immunosuppressive drugs might ultimately harm more patients than they help. Several agents, including anti-TNF-α, have been tried in other infections that cause septic shock, with mixed results. In some patients anti-TNF-α seemed to do more harm than good. But Jean-Louis Vincent, a sepsis expert at the Free University of Brussels, points out that these studies were done in patients with septic shock of various origins, all at different stages in the chaotic progression of the immune system from friend to enemy. The key to treatment may be timing, he says, boosting the immune response before it has run amok, and damping it down later.
Careful monitoring of key cytokines might reveal when to intensify the battle, or end it. “We need to dissect the cascade of immune reactions, and interfere [using] something more sophisticated than corticosteroids,” says Osterhaus. “We don’t understand the whole story – but we’re on the right track.”
