̽��ֱ�� of Cambridge - Leah Katzelnick

Global consortium rewrites the ‘cartography’ of dengue virus

cjb250 — Thu, 17 Sep 2015 18:00:11 +0000

Dengue virus infects up to 390 million people each year. Around a quarter of these people will experience fever, headaches and joint pains, but approximately 500,000 people will experience potentially life-threatening complications, including haemorrhage and shock, where dangerously low blood pressure occurs. There are currently no vaccines against infection with dengue virus.

For decades, scientists have thought that there are four genetically-distinct types of the virus, known as serotypes, and that antigenic differences between the types play a key role in the severity of disease, its epidemiology and how the virus evolves – and hence these differences would be important in vaccine design.

When we become infected, our immune system sends out antibodies to try and identify the nature of the infection. If it is a pathogen – a virus or bacteria – that we have previously encountered, the antibodies will recognise the invader by antigens on its surface and set of a cascade of defences to prevent the infection taking hold. However, as pathogens evolve, they can change their antigens and disguise themselves against detection.

One of the unusual aspects of dengue is that in some cases when an individual becomes infected for a second time, rather than being immune to infection, the disease can be much more severe. One hypothesis to explain this is that the antibodies produced in response to infection with one strain of the virus somehow allow viruses of a different strain to enter undetected into cells, implying that antigenic differences between the serotypes are important.

Researchers from the Dengue Antigenic Cartography Consortium, writing in today’s edition of Science, analysed 47 strains of dengue virus with 148 samples taken from both humans and primates to see whether they indeed fit into four distinct types. ̽��ֱ��researchers found a significant amount of antigenic difference within each dengue serotype – in fact, the amount of difference within each serotype was of a similar order to that between the different types. This implies that an individual infected with one type may not be protected against antigenically different viruses of the same type, and that in some cases the individual may be protected against some antigenically similar strains of a different type.

Leah Katzelnick, a researcher from the Department of Zoology at the ̽��ֱ�� of Cambridge, who began studying dengue after herself contracting the disease, says: “We were surprised at how much variation we saw not only between the existing four known types of dengue, but also within each type. This means that hypotheses that put antigenic differences at the centre of dengue epidemiology are now back on the table.”

Senior author Professor Derek Smith, also from the Department of Zoology at Cambridge, adds: “This discovery is in many ways similar to when researchers first began using the microscope – it will give us a new way of looking at dengue and in much closer detail than before. Now we can ask – and potentially answer – the interesting questions about how the virus evolves and, importantly, why a first dengue infection is often mild while many second infections are life-threatening.”

Characterising the global variation of dengue viruses will be important for understanding where current vaccines will be protective. In the future, it may assist us in determining which strain to include in vaccination programmes and to follow the virus as it evolves, say the researchers.

̽��ֱ��Dengue Antigenic Cartography Consortium is an open, global collaboration of dengue researchers set up in 2011 to establish how large samples of dengue isolates relate to one another antigenically. ̽��ֱ��Consortium currently consists of epidemiologists, clinicians, geneticists, cartographers, molecular biologists, government officials, and vaccine developers, based in laboratories in Africa, the Americas, Asia, Europe, and the Pacific. As results from the project become available, they are shared with members of the Consortium.

Reference
Katzelnick, LC et al. Dengue viruses cluster antigenically but not as discrete serotypes. Science; 17 Sept 2015.

An international consortium of laboratories worldwide that are studying the differences among dengue viruses has shown that while the long-held view that there are four genetically-distinct types of the virus holds, far more important are the differences in their antigenic properties – the ‘coats’ that the viruses wear that help our immune systems identify them.

This discovery is in many ways similar to when researchers first began using the microscope – it will give us a new way of looking at dengue and in much closer detail than before

Derek Smith

JAVIER DEVILMAN

Aedes Albopictus mosquito (cropped, lightened)

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A very personal perspective on Dengue fever

cjb250 — Tue, 20 Jan 2015 00:00:28 +0000

Dengue outbreaks, caused by bites from infected mosquitoes, are common in many developing countries. Four billion people live in areas with the disease, although mortality is relatively low. There are 400 million infections a year: 500,000 people develop severe infection symptoms and approximately 25,000 of these die. However, it places a huge burden on the health services of countries where there are major outbreaks. “Epidemics can swamp public health and intensive care services,” says Leah. “They create fear even if there is a low likelihood of death and in many countries virtually everyone knows someone who has died from it, most of whom are children.”

For her PhD she has been working with both human and non-human primate sera in partnership with the US-based National Institutes of Health. Isolates from some of the main strains of the dengue virus are injected and Leah studies the immune sera to chart the inter-relationship between the four main strains of the virus. Dengue only causes mild infection in the non-human primates she works with.

Leah, who majored in anthropology as an undergraduate in the US, travelled to Nicaragua in her third year as part of a summer fellowship programme on international health. Her aim was to learn about different health systems and beliefs about health. Her research involved talking to people in non-governmental organisations (NGOs) about their aims and talking to people on the ground about how the NGOs were perceived. Then she contracted dengue fever and became very sick and was admitted to hospital.

“There is no cure for dengue and only the symptoms can be treated. In the most mild cases dengue is asymptomatic. Normally people suffer from joint ache, headaches, pain behind the eyes and a strange rash on the hands. In the most extreme cases they suffer from haemorrhagic fever and a rapid drop in platelet count and blood pressure which can cause the body to go into shock. Children who go into shock have a high mortality rate, but if they get good healthcare they can survive,” says Leah.

She spent a week in hospital being monitored for possible shock. Her vascular system was so traumatised afterwards that she felt very weak. ̽��ֱ��experience led to her doing a lot of research on dengue fever and caused her to rethink her future since people who have been exposed to dengue fever before are more likely to suffer the more extreme form the next time round. As an anthropologist she would have needed to travel and mainly to places where there was dengue fever, but she did not want to risk getting it again.

Leah applied for a fellowship from Williams College in the US to study at Cambridge and spent the summer before in a dengue laboratory in North Carolina estimating transmission of dengue fever in Sri Lanka.

Once at Cambridge, she googled dengue fever research on the university website and the only person she came across who mentioned it was Professor Derek Smith, who studies infectious disease in the Department of Zoology. She read his paper on antigenic cartography and the evolution of flu viruses and felt it could be applied to the four different types of dengue and the complex interaction between those types. She wanted to design an antigenic map for dengue which would show the relationship between the different viruses and how having one might protect you from having that same strain again while having the others could make your feel worse.

She emailed Professor Smith and put her proposal to him. He said there was no funding for a project on dengue. However, Leah’s fellowship allowed her to switch the focus of her studies after a year. That meant she could get funding for a year. She then applied to do a PhD to continue her work and for a Gates Cambridge Scholarship to support her.

Leah began her PhD in 2012 and hopes to complete it next year. She has been working round the clock on her research and says it was initially terrifying since her background was in anthropology rather than lab-based science. Since then she has been presenting her findings at international meetings such as the World Health Organization and has submitted a paper for review to a top journal. She plans to keep working on dengue fever after her PhD is completed and to better understand the human immune response to dengue virus infection so that scientists can limit its impact.

Leah Katzelnick was all set for a career as an anthropologist until she contracted dengue fever. She was in hospital for a week with severe symptoms. It changed her life. She is now working on a new perspective on dengue fever which involves mapping the complex interaction between different strains of the virus, based on similar work done by Cambridge experts on flu.

There is no cure for dengue and only the symptoms can be treated

Leah Katzelnick

James Gathany

Aedes aegypti mosquito

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