Dengue Manages Resistance Through Mutations in One Protein

Duke-NUS Researchers Find Virus Changes its Shape to Resist Vaccines and Drugs

Micrographs of DENV2 with different distribution of smooth and bumpy surfaced particles when incubated at different temperatures to mimic (L-R) mosquitoes (29°C), human host (37°C) and human with a fever (40°C). Credit: Xin-Ni Lim, Duke-NUS Medical School
Micrographs of DENV2 with different distribution of smooth and bumpy surfaced particles when incubated at different temperatures to mimic (L-R) mosquitoes (29°C), human host (37°C) and human with a fever (40°C). Credit: Xin-Ni Lim, Duke-NUS Medical School

SINGAPORE – The dengue virus changes its surface from smooth to bumpy to evade vaccines and therapeutics, according to new research from Duke-NUS Medical School (Duke-NUS), the Agency for Science, Technology and Research (A*STAR)’s Bioinformatics Institute (BII), and the University of Texas Medical Branch (UTMB)..

The study also gives insights on treatment strategies to use at different stages of infection, which might lead to new vaccine development and treatments for dengue disease.

Dengue virus (DENV) infects about 400 million people annually around the world, with a high prevalence in tropical and sub-tropical regions. The virus causes diseases ranging from mild dengue fever to severe dengue hemorrhagic fever and dengue shock syndrome.

The virus appears smooth and spherical  while growing in a mosquito at 29 degrees Celsius. Upon entering a human body at 37C, it changes to a bumpy surface which helps the virus to evade the immune system of the human host. These changes come from mutations in the envelope protein on the outer shell of the virus particle.

The researchers wanted to understand how it changes from smooth to bumpy.

“Together with Professor Pei-Yong Shi from UTMB, we found that in laboratory developed DENV2 strains, mutations in the virus’ envelope protein causes its transformation into bumpy particles,” said Xin-Ni Lim, the study’s lead author, who is from Duke-NUS’ Emerging Infectious Diseases (EID) Programme. “These structural changes can cause vaccines and therapeutics to be ineffective against the virus.”

The team also tested four DENV2 strains obtained from patients. They found that most of these strains maintained smooth surface structure at 37 degrees Celsius. However, at 40 degrees Celsius, the temperature of a fever, they took on a bumpy surface.

“Our study gives a new direction to vaccine development and treatment for dengue disease,” said Shee-mei Lok, a Duke-NUS professor. “For prevention of disease through vaccines that are administered to the patient before dengue infection, we should use those that are effective against the smooth-surface virus. When it comes to patients displaying fever symptoms, treatment strategies effective against the bumpy surface particles should be implemented,” she said.

“This study is a first step towards gaining more insight into how DENV2 reacts and adapts to the host’s immunological defenses,” said Peter Bond, Principal Investigator from A*STAR’s BII. “We were also able to use computational modelling to predict why particles from different DENV2 strains are more or less adept at morphing from the smooth to bumpy structures. By better understanding the interactions between the virus and the host, we will be able to develop better therapies and vaccines to treat or prevent infections, and contribute to public health outcomes.”

The study’s findings also show that the lab-adapted DENV2 may not be a good model for research, as its structure is different from the clinical strains isolated from patients. The team is planning to study the other DENV serotypes to find out if there are any other possible structural changes.

CITATION: "Molecular basis of dengue virus serotype 2 morphological switch from 29°C to 37°C," Lim X, Shan C, Marzinek JK, Dong H, Ng TS, Ooi JSG, Fibriansah G, Wang J, Verma CS, Bond PJ, Shi P and Lok S. PLOS Pathogen, Sept. 19, 2019. DOI: 10.1371/journal.ppat.1007996

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007996