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The nuts and bolts of immune response to dengue: Gaining insight into the disease

Urvashi Bhattacharyya

A sketch showing the dengue virus being destroyed by a macrophage after being covered by antibodies. T and B cells are in the periphery.
A sketch showing the dengue virus being destroyed by a macrophage after being covered by antibodies. T and B cells are in the periphery.   (Photo: Sharanya Soundararajan)

The official report of dengue cases in India stands at about 20000 a year. With an estimated annual economic burden of nearly US$ 1.11 billion and an increasing number of outbreaks, fighting dengue is by no means an easy mountain to climb. Dengue is caused by the bite of the dengue virus (DENV) carrying mosquito, Aedes aegypti. There are 4 strains, or serotypes, of the virus that can be distinguished through blood analysis. Persons infected once with a single serotype of DENV show enhanced inflammatory responses upon secondary infections with another DENV serotype. Apart from inadequate public health measures, a comprehensive lack of knowledge about factors responsible for severity of infection in India also limit our arsenal in effectively fighting the disease. 

A detailed insight into the viral and immune factors causing severity can help in early diagnosis. This task was undertaken recently by researchers from All India Institute of Medical Sciences (AIIMS), Translational Health Science and Technology Institute (THSTI), Institute of Genomics and Integrative Biology (IGIB) and International Centre for Genetic Engineering and Biotechnology (ICGEB). The results of their study, published in PLOS Neglected Tropical Diseases, highlights the difference between disease severity and its relation with viral serotypes as well as immune responses of the body.

Guruprasad Medigeshi, who led the study from THSTI explained, “We pursued this study since there is no extensive characterisation of dengue versus immune response in the Indian population, be it adults or children. The intuition was to look at the paediatric infection in India as the young are most susceptible. We investigated the factors that are either responsible for, or occur due to severe infection.” 

The researchers collected blood samples from a cohort of 97 children that showed varying levels of disease severity according to WHO standards: Severe Dengue (SD), Dengue Illness (DI) and Dengue with Warning Signs (DW). 60% of the patients had secondary infections with a majority having serotype 2 DENV. Counterintuitively, almost all of the secondary cases, but only about a third of the primary cases, were severe. What then distinguishes primary and secondary infections and how do these clinical symptoms manifest themselves with viral and immune factors? 

The researchers compared viremia—the amount of virus in blood—with factors like disease severity, platelet count and various blood factors. Viremia in these infections was found to be uncorrelated with disease severity, even though it was higher in secondary infections compared to the primary ones. Further, low platelet count, one of the hallmarks of dengue was more marked in patients with secondary infections and high viral load than in patients with low viral counts. The researchers believe it to be likely that DENV causes a decrease in platelet count by directly altering/affecting their function. 

Apart from platelet counts, the investigators also studied the effect on cytokines, a group of small proteins that mediate immune response and help in directing immune cell movement to the site of infection. Interleukins (IL) and interferons (IFN)—classes of cytokines—were shown to be associated with disease severity at different levels. “Dengue severity may either cause interferon levels to drop, or people with low interferon levels might be a susceptible population to dengue infections,” believes Medigeshi. In either event, interferon therapy may help in recovery of such cases. The authors also identified additional markers of disease severity using a bio-informatics approach of assigning importance to serum factors, based on their ability to predict severity and classifying them accordingly.

These findings can help understand and aid diagnosis of dengue better. “Through a systematic measurement of baseline factors, pre-disposability to dengue can be detected and target population identified very early in infection,” said Medigeshi. Early detection of dengue severity with a timely anti-viral treatment can help in better management of a disease that cripples health services in India every year.