January 14, 2014 -- The dengue virus infects almost 400 million people annually and is a major health concern in Singapore. Currently the World Health Organization recommends vector control as the primary way to prevent dengue as some of these infections go on to become life threatening. Dengue vaccines are being developed to target endemic dengue but are complicated by the presence of four different dengue strains since these vaccines can only target a single strain at a time.
For the first time Associate Professor Ooi Eng Eong of Duke-NUS Graduate Medical School and his team may have found a way to target all four strains. Their recent study, published in the journal Proceedings of the National Academy of Sciences USA, demonstrates how the dengue virus evades the immune response that would otherwise be triggered by antibodies. While additional work would still be required for full clinical translation, this discovery could potentially shape vaccine design.
When a person is infected by one strain, it makes them immune from that strain but alarmingly even more susceptible to the others. The reason for this is that each strain can take advantage of antibodies that we develop when we are infected by another strain by using them to enhance its own entry into our white blood cells. Exactly how the dengue virus exploits antibodies to its advantage is not fully understood and this has hampered vaccine development in the past.
The research led by Assoc Prof Ooi, who is also Deputy Director of the Emerging Infectious Disease Program at Duke-NUS, uncovered the mechanism that the dengue virus employs to evade the immune response otherwise triggered by antibodies. Their research showed that white blood cells naturally activate its internal immune defenses when it engulfs antibody-bound viruses from the blood circulation. To overcome these early immune defenses, the dengue virus binds and activates an inhibitory receptor that dampens our immune response during infection. This inhibitory receptor is present on white blood cells and its normal function is to prevent excessive activation of the immune response. By activating this naturally present inhibitory receptor, the dengue virus enters white blood cells using the antibodies that developed from a previous infection but without triggering the immune response that would otherwise suppress its replication. These findings suggest that strategies that block the dengue virus from activating this inhibitory receptor would render a more efficient immune clearance of the virus.
Annex A: Summary of the study
When a person is vaccinated against or re-infected by a virus their immune system, triggered by antibodies, defends their body against it.
This doesn’t happen with dengue. When a person is vaccinated against or infected by one of four serotypes and then are infected by another serotype at a later time, the infection is typically worse because dengue manages to shut down the immune system response.
Discovery
For the first time, Dr Ooi Eng Eong’s team has discovered how dengue exploits antibodies to its advantage by uncovering the mechanism it uses to bypass the immune system. The dengue virus binds and activates an inhibitory receptor LILRB1 (leukocyte immunoglobulin-like receptor-B1).
Dengue virus immune system shutdown process
- Viruses which are antibody-bound typically enter the bloodstream and activate the Fc receptor which causes white blood cells to raise immune defenses
- To overcome this the dengue virus binds and activates LILRB1
- LILRB1 blocks the Fc receptor from over-activating the immune system response
- This allows the dengue virus to replicate and ensure its survival, resulting in a more severe reinfection.
Implications
This is the first time the mechanism has been uncovered. It explains the behavior of the dengue virus and why vaccine development is so complicated.
Currently dengue vaccines try and replicate the entire virus. Strategies that block the dengue virus from activating LILRB1 would render a more efficient immune clearance system of the virus.
If vaccines could be engineered to produce antibodies that block dengue virus from binding to and hence activating LILRB1, the risk of antibody-enhanced infection following vaccination would be reduced. This would alleviate a major safety concern in dengue vaccination.
Next step
Dr Ooi and his team are currently studying exactly which part of the dengue virus binds to which part of LILRB1. Upon locating this site, the knowledge can be used to develop a more targeted vaccine therapy.
Full Title: Dr Ooi Eng Eong, Associate Professor and Deputy Director of the Emerging Infectious Diseases Program, Duke-NUS Graduate Medical School
Funding: National Medical Research Council
Journal: Proceedings of the National Academy of Sciences USA, to be published in the week of January 13, 2014.
For media queries, please contact:
Dharshini Subbiah
Email: dharshini.subbiah@duke-nus.edu.sg
Tel: (65) 6601-3272
About Duke-NUS Graduate Medical School
The Duke-NUS Graduate Medical School Singapore (Duke-NUS) was established in 2005 as a strategic collaboration between the Duke University School of Medicine, located in North Carolina, USA and the National University of Singapore (NUS). Duke-NUS offers a graduate-entry, 4-year M.D. (Doctor of Medicine) training program based on the unique Duke model of education, with one year dedicated to independent study and research projects of a basic science or clinical nature. Duke-NUS also offers M.D/PhD and PhD programs. As a player in Singapore’s biomedical community, Duke-NUS has identified five Signature Research Programs: Cancer & Stem Cell Biology, Neuroscience and Behavioral Disorders, Emerging Infectious Diseases, Cardiovascular & Metabolic Disorders, and Health Services and Systems Research.
Duke-NUS and SingHealth have established a strategic partnership in academic medicine that will guide and promote the future of medicine, tapping on and combining the collective strengths of SingHealth’s clinical expertise and Duke-NUS’ biomedical sciences research and medical education capabilities.
For more information, please visit www.duke-nus.edu.sg
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