Dengue viral infections are one of the most rapidly emerging mosquito borne viral infections in the world, resulting in a huge economic burden in affected countries. Currently there is no licensed vaccine to prevent dengue, nor an effective specific drug for its treatment. Severe forms of dengue infection is characterized by vascular leak leading to shock and haemorrhage, which is thought to occur as a result of complex interactions between the virus, host genetics and the immune system. Innate like lymphoid cells (ILCs) are a recently identified population of haematopoietic effector lymphoid cells, which are predominantly tissue resident. The ILC subtype that predominantly produces type 2 cytokines (IL-4, IL-5 and IL-13) are known as ILC type 2 (ILC2s) and have shown to be important in the pathogenesis of atopic eczema and allergic asthma. Elevated type 2 cytokines are present in the blood of individuals with acute severe dengue suggesting that ILC2 could be a source. Although the source of these cytokines was previously thought to be from Th2 cells, we found that dengue- specific T cells are not the primary source of these cytokines in acute infection. Preliminary investigations done by Graham Ogg?s lab in ILC2s in acute dengue infection, showed that ILC2s are greatly expanded in patients with acute dengue infection, when compared to healthy seronegative individuals, in whom ILC2s are rarely detected in peripheral blood. In addition, the frequency of ILC2s negatively correlated with platelet counts, which is a marker of disease severity. It has been shown that monocytes and dendritic cells, are significantly more permissive to infection with the dengue virus in the presence of IL-4 and IL-13. In acute dengue infection, monocytes and dendritic cells have shown to be the main cell types infected with the virus. In addition, studies on determining risk factors for hospitalization due to dengue infection in a large cohort of individuals (n=1689) in Sri Lanka done by Gathsaurie Malavige?s group, showed that both bronchial asthma and allergic rhinitis were significantly associated with a higher risk. Collectively, these data suggest that since ILC2s are greatly expanded during acute dengue infection and since monocytes and dendritic cells are more permissive to infection in the presence of type 2 cytokines, ILC2s could be playing a role in the pathogenesis of acute dengue. By understanding the role of ILC2 in disease pathogenesis, we aim to identify new targets for therapeutic intervention.

Public Health Relevance

Dengue virus infects 390 million of the global population annually, and has considerable associated morbidity, mortality and health economic burden for individuals and international health resources. The research addresses mechanisms underlying dengue-associated inflammation and therefore potentially has an impact internationally for patients and the academic community. By understanding such mechanisms underlying dengue-associated disease, we will identify new targets for therapeutic intervention.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-IMM-M (90))
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Challberg, Mark D
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University of Oxford
United Kingdom
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OX1 2-JD