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Discovering a Survival Technique of the Dengue Virus

Duke-NUS team discovers that dengue virus strains may evade vaccines and treatments through a mysterious transforming ability.

While global efforts to suppress the spread of COVID-19 have been front and centre for most of 2020, the fight against other viruses and seasonal diseases continues. In Singapore, dengue fever has been on the rise, with infection rates approaching their highest levels in years.

In a new study from Duke-NUS Medical School (Duke-NUS), scientists from the Emerging Infectious Diseases (EID) programme found that the dengue virus serotype 3 (DENV3) can dramatically alter its structure depending on host conditions, allowing it to develop resistance against vaccines and therapeutics. This finding could help in the development of counter-measures against DENV and other pathogenic viruses.

Even without the added challenge of structural transformation of DENV serotypes, there are several factors that make developing approaches against dengue difficult. There are four known serotypes of the dengue virus (DENV1-4), which can all be found globally. Each DENV serotype is characterised based on the type and number of their surface antigens. Furthermore, each serotype consists of several different strains, which vary in structure, further allowing the virus to evade host immune systems and complicating the development of therapeutics.

The difficulty in developing DENV vaccines or therapeutic agents lies in taking all four DENV serotypes into consideration. Targeting one serotype by producing antibodies against it only protects against that specific serotype, leaving the individual susceptible to other DENV serotypes.

Of even greater concern, the severity of dengue symptoms is usually exacerbated in an individual who is vaccinated against or who has recovered from one DENV serotype, but is infected by a different serotype later. To prevent this situation, an effective vaccine would need to target all four serotypes to similar extents.

Most past research conducted in Singapore on dengue has focused on DENV2 as this used to be the predominant serotype, but infections from DENV3 are becoming increasingly common. A previous study by the Duke-NUS team found that the DENV2 serotype has the ability to alter its surface morphology from smooth to bumpy. “Previous structural work focused mostly on DENV2, and therefore the other serotypes that are equally important are not well studied,” said Professor Shee-mei Lok from Duke-NUS’ EID programme.

Professor Lok is also the corresponding author of this study which was published in Nature Communications in June 2020. On her team’s new findings, she explains: “In this study, we found that DENV3 can dramatically transform itself from a smooth, round particle to a club-shaped particle – like golf clubs, which would help the virus to evade hosts’ immune response, vaccines and therapeutics.”

In particular, some strains of DENV2 and DENV3 were found to change their surface morphology depending on temperature, having different structures at different physiological temperatures of mosquitoes and of humans.

DENV1-4 are part of the Flavivirus genus, which also includes other notorious pathogens such as the Zika, West Nile, and yellow fever viruses. Members of this genus are positive-sense single-stranded RNA viruses, which are usually transmitted by arthropods such as mosquitoes and ticks.

Besides DENV3, the team also found that certain strains of DENV1, DENV2 and the Zika virus can also transform into club-shaped particles, potentially conferring on them resistance against vaccines and therapeutics, although fortunately this transformation ability is not often observed among viruses.

Based on their findings, the Duke-NUS team is now studying if more DENV3 strains are able to undergo similar structural transformations.

This study provides exciting insights about pathogens and flaviviruses, potentially driving new developments in vaccine and therapeutics design. “While Singapore has seen a recent spike in dengue cases, annually this virus infects about 400 million people worldwide, with a high prevalence in tropical and sub-tropical regions. In line with Duke-NUS’ vision of transforming medicine, this study gives new direction to developing better therapies and vaccines to treat or prevent dengue infections, and contribute to public health outcomes,” said Professor Patrick Casey, the Senior Vice Dean for Research at Duke-NUS. [APBN]