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Scientists now know why a second dengue infection is much more severe than the first.
The long-kept secrets of the dengue virus — which affects between 50 and 100 million people every year — are tumbling out.
Scientists have long wondered why a re-infection (in the same or subsequent year) causes more complications, even becoming fatal, than when it strikes the first time. The puzzle has been finally solved — by two independent research teams. The knowledge gained by the scientists is expected to help design drugs and vaccines against dengue fever, which currently has no treatment.
Normally, viruses — which have very little genetic material of their own — co-opt the host’s genetic machinery to survive and replicate. More often than not, if the host has an efficient immune system, the invaders are destroyed. In most cases, the antibodies produced by the body stay for long, if not permanently, and fight off any subsequent attack by the same virus. But in the case of dengue, the second infection proves to be much more severe than the first.
Back in the 1970s, US virologist Scott Halstead hypothesised that the dengue virus may be receiving help from the very antibodies that are supposed to fight the infection. Halstead termed the phenomenon antibody-dependent enhancement (ADE) of infection. He got an inkling of this during his extensive clinical studies in Thailand in the 1960s.
For a good part of the ensuing four decades, Halstead’s assumption remained mere theory. But in February this year, Sujan Shresta, a Nepal-born virologist at the La Jolla Institute of Allergy and Immunology in California, came up with conclusive proof for Halstead’s hypothesis. “It’s a situation where antibodies can be bad for you — it’s counter to everything we know about the normal function of antibodies,” she says.
Dengue infection is transmitted by the Aedes aegypti mosquito. There are four known strains of the virus circulating in the world. Infection can cause diseases ranging from dengue fever, a flu-like illness, to the severest form — dengue haemorrhagic fever or dengue shock syndrome. The latter can cause the blood vessels to leak, leading to life-threatening shock. It is estimated that 2.5 billion people — that is, two-fifth of the world’s population — live in regions where dengue fever is rampant. While it is more common in South East Asia and South America, the incidence is rising in India too. Since 1996, the country had witnessed a number of dengue outbreaks and a few hundred Indians die of dengue-related complications every year.
Shresta’s team at La Jolla developed the first ever mouse model to study the disease. The scientists conducted experiments to prove that certain antibodies produced by the body against the virus indeed exacerbate the condition. The four strains of the virus circulate simultaneously, says Shresta. Infection with one provides lifelong immunity against that particular strain. In subsequent infections, where a different strain of the virus is involved, the antibodies do not recognise enough of the virus to neutralise it. “This starts a cascade of unusual molecular events — the ADE process — which leads to the antibodies contributing to, rather than fighting, the infection,” she explains.
Taking the research forward, a team of UK and Thai scientists identified specific antibodies involved in the ADE process. The study, reported early this month in the journal Science, showed that the culprits are antibodies against a particular viral protein called precursor membrane protein (prM). According to the researchers, if the antibodies are present in the body, the infection spreads faster with the antibodies against prM helping the virus infect more host cells. In fact, there is a several hundred-fold increase in the number of infected cells in the presence of the antibodies, they say.
“This is a significant piece of work. It shows the exact region for the enhancement — which is the prM, and not the E region of the virus, as we have been thinking so long,” says Shamala Devi Sekaran, a virologist at the University of Malaysia who has been studying the dengue virus for years.
“The study pinpoints the nature of the antibodies that are likely to cause the severest form of the disease in humans,” says Shresta. It will greatly help those trying to develop vaccines against dengue, she adds.
“Our research gives us some key information about what is not likely to work when trying to combat the virus. We hope our findings will bring scientists one step closer to creating an effective vaccine,” says Gavin Screaton, head of medicine, Imperial College London, and lead author of the study.
The biggest challenge is that the dengue vaccine will need to provide immunity against all the four strains of the virus at the same time. “If protection is incomplete, the vaccine can potentially protect against some viruses but leave the individual primed for a more severe outcome if he or she is infected with the others,” Screaton told Knowhow.
In addition to these developments, there have been two recent breakthroughs in controlling the dengue mosquito. Oxford University scientists developed sterile male Aedes aegypti mosquitoes which have undergone successful semi-field trials in Asia. And scientists at the University of Queensland developed a mutant strain of a bacterium called Wolbachia, which halves the adult life span of female Aedes aegypti mosquitoes in laboratory conditions.
Source: The Teleghraph ( Kolkata, India)
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