A recent study sheds light on how natural killer T cells play a crucial role in shaping the immune response to the dengue virus, potentially mitigating the severity of future infections.
As the dengue virus remains a major global health threat, an international research team from Duke-NUS Medical School has uncovered an important connection between the body’s first immune response and its ability to fend off reinfections. The researchers discovered that natural killer T (NKT) cells can determine whether the immune response creates protective antibodies that neutralize the virus or detrimental ones that might worsen the disease during future infections.
Dengue fever, prevalent in tropical and subtropical areas, is caused by four closely related serotypes of the dengue virus. A person infected with one serotype does not gain immunity to the others, which means they can suffer reinfection from a different serotype. Such secondary infections are known to increase the risk of developing severe disease.
Associate Professor Ashley St John from the Programme in Emerging Infectious Diseases at Duke-NUS, who is a senior author of the study published in the Journal of Clinical Investigation, provided a summary of the findings:
“Our research indicates that NKT cells not only influence the immune response to an initial dengue infection but are also crucial in determining how severe future infections might be. Understanding this mechanism is vital, as it could lead to improved strategies for protecting communities, particularly in regions where dengue is endemic, where severe reinfections can burden healthcare systems and affect public health.”
Fighting primary infections and enhancing the body’s defenses against reinfections
The researchers noted that individuals infected with dengue have high levels of NKT cells present in their skin, the initial entry point of the virus. While many immune cells respond to the infection, NKT cells are among the first responders. These unique immune cells integrate elements of both natural killer cells and T cells, bridging the innate and adaptive immune systems while playing a key role in governing immune responses.
When NKT cells are activated during the primary dengue infection, they contribute to forming strong immune memory that helps protect against future infections. Simply put, NKT cells recruited to the skin at the onset of infection can influence immune responses for months or even years afterward.
Besides fighting the virus directly in the skin, NKT cells also promote a beneficial immune environment in nearby lymph nodes. This aids other immune cells in producing effective antibodies that are essential for neutralizing the virus and ensuring long-term protection.
The immune system relies on two primary types of responses: Th1, which focuses on eliminating threats after they infect cells, and Th2, which addresses pathogens like bacteria and parasites outside the cells. Th1 responses are particularly effective against viruses such as dengue. The researchers found that NKT cells drive dengue-specific Th1 responses, resulting in the creation of effective antibodies that neutralize the virus.
In their pre-clinical model, the team observed that immune systems lacking functional NKT cells tended to produce Th2-type antibodies, which are less effective against viruses. This results in inadequate protection against reinfections from the same strain. More importantly, it can lead to a phenomenon known as antibody-dependent enhancement, where the “bad” antibodies from the initial infection worsen the disease in later infections with different strains. This can make a second dengue infection more severe than the first.
Similar trends were noted in humans. Patients experiencing primary dengue infections who developed Th1-associated antibodies (linked to NKT cell activity) had better health outcomes, while those with secondary infections who produced high levels of Th2-associated antibodies were more likely to suffer severe illness.
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 Centre, stated:
“Understanding how immune cells generate strong early responses can aid in designing vaccines that leverage NKT cells and Th1 responses to enhance antibody and memory cell production. This method could improve the effectiveness and safety of dengue vaccines, especially for those previously exposed, and enable personalized treatment by tracking antibody levels to assess the risk of severe disease.”
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, remarked:
“These insights represent a significant step forward in our fight against dengue and demonstrate Duke-NUS’ commitment to developing innovative solutions to global health challenges. They not only lay the groundwork for creating better vaccines and personalized treatments for dengue but could also have wider implications for tackling other viral diseases.”
Recognizing that early immune responses can significantly impact long-term health and immune memory may also hold relevance for other viruses, such as influenza and COVID-19, where a robust immune memory is vital. However, further research is needed to explore how these findings relate to other viral infections.
Duke-NUS is a leading biomedical research institution that merges fundamental scientific research with practical applications to transform the management of common infections like dengue in clinical settings.
