As the dengue virus continues to be a significant global health concern, an international research team led by Duke-NUS Medical School has identified a critical link between the body’s initial immune response and its defense against reinfections.

Researchers found that natural killer T (NKT) cells influence whether the response generates protective antibodies that neutralize the virus or harmful ones that could exacerbate the disease in future infections.

Particularly rampant in tropical and subtropical regions, dengue fever is caused by four closely related but distinct types of the dengue virus, known as serotypes. An initial infection with one serotype does not provide immunity against the others, so a person can be reinfected by a different serotype. Secondary infections are a well-known risk factor for developing severe disease.

Associate Professor Ashley St John from the Program in Emerging Infectious Diseases at Duke-NUS, is senior author of the study published in the Journal of Clinical Investigation.

“Our study shows that NKT cells not only shape the immune response to an initial dengue infection but also play a pivotal role in determining the severity of future infections.

“Understanding this process is crucial, as it can lead to better strategies for protecting communities, especially in dengue-endemic regions, where severe reinfections can strain health care systems and impact public health,” says St John.

Combating a primary infection and fortifying the body against reinfections

The researchers were intrigued by the fact that people infected with dengue have high concentrations of NKT cells in their skin, where the virus initially enters the body. Although many immune cells respond to the infection, NKT cells are among the first to act. Integrating features of both natural killer cells and T cells, these unique immune cells link the innate and adaptive immune systems and play a key role in regulating immune responses.

When NKT cells are active during the initial dengue infection, they help establish a strong immune memory that protects against subsequent infections. In other words, NKT cells recruited to the skin at the start of an infection can influence immune responses for months or even years.

In addition to combating the virus directly in the skin, NKT cells also help to establish a supportive immune environment in nearby lymph nodes. This facilitates the production of effective antibodies, which are essential for neutralizing the virus and providing long-term protection by other immune cells.

The immune system relies on two primary types of immune responses—Th1, which focuses on destroying threats once they have infected cells, and Th2, which combats pathogens like bacteria, parasites and toxins outside cells. This makes Th1 responses particularly effective against viruses such as dengue. The researchers discovered that NKT cells drive dengue-specific Th1 responses, leading to the production of “good” antibodies that neutralize the virus.

In a pre-clinical model, the team found that the immune systems lacking functional NKT cells produce Th2-type antibodies, which are less effective against viruses. This leads to inadequate protection against reinfection with the same strain.

More importantly, it can also cause a phenomenon known as antibody-dependent enhancement, where “bad” antibodies from the initial infection exacerbate the disease during later infections with different strains. This can make a secondary dengue infection more severe than the initial one.

Similar patterns were also observed in humans. Patients with primary dengue infections who developed Th1-associated antibodies, linked to NKT cell activity, had better outcomes, whereas those with secondary infections who produced high levels of Th2-associated antibodies were more likely to experience severe disease.

Co-senior author and Adjunct Senior Research Fellow at Duke-NUS, Dr. Abhay Rathore, who is also from the Department of Pathology at Duke University Medical Center, said, “Understanding how immune cells generate strong early responses can help us design vaccines that utilize NKT cells and Th1 responses for better antibody and memory cell production.

“This approach could enhance dengue vaccine effectiveness and safety, especially for those with prior exposure, and allow for personalized treatment by monitoring antibody levels to assess the risk of severe disease.”

Professor Patrick Tan, senior vice-dean for research at Duke-NUS, commented, “These findings mark a significant advance in our battle against dengue and reflect Duke-NUS’ dedication to pioneering innovative solutions to global health challenges.

“They not only pave the way for developing more effective vaccines and personalized treatments for dengue but could also have potential implications for other viral diseases as well.”

Recognizing that early immune responses can affect long-term health and the nature of immune memory may also be relevant for viruses such as influenza and COVID-19, where strong immune memory is crucial. However, additional research is needed to determine the relevance of these findings to other viral infections.