This study reveals features of protective immune responses during secondary dengue infections through single-cell immune analysis, including expansion of CD4+ TEMRA cells, enhanced Treg function, and upregulation of type I interferon responses. Meanwhile, hospitalized patients showed dysfunctional CD8+ memory T cells and expansion of plasmablasts. These findings provide new adaptive immune markers for dengue vaccine development.
Literature Overview
This article, 'Immune Features of Asymptomatic Secondary Dengue Infections Reveal Adaptive Immune Signals Associated with Protection from Severe Dengue,' published in Cell Host & Microbe, reviews and summarizes immune differences associated with different clinical outcomes following dengue infection, with a particular focus on adaptive immune features in asymptomatic and hospitalized patients. The study found that asymptomatic individuals have higher frequencies of DENV-specific CD4+ T cells and increased expression of Treg function-related genes, whereas hospitalized patients exhibit high proliferation but low cytotoxicity in CD8+ memory T cells and significant expansion of IgG1+ plasmablasts. These findings offer new insights for the development of T cell-based dengue vaccines and therapeutic strategies.Background Knowledge
Dengue is a mosquito-borne infectious disease caused by the dengue virus (DENV), with more than half of the global population at risk of infection. Secondary heterologous infections are associated with more severe clinical symptoms, and adaptive immune responses play a dual role in disease progression. Previous studies have identified correlations between HLA molecule expression, the magnitude and multifunctionality of DENV-specific T cell responses, and protection against dengue. However, the immune mechanisms underlying asymptomatic infections remain poorly understood, posing challenges for vaccine and therapeutic development. This study systematically compares immune features between asymptomatic and hospitalized patients using single-cell RNA sequencing combined with BCR and TCR analysis, aiming to identify adaptive immune signatures associated with disease severity and provide new candidate targets for dengue vaccine development.
Research Methods and Experiments
The research team collected blood samples from dengue-infected patients in Cambodia during 2018–2019 and 2022–2023, including asymptomatic groups (n=6 and n=17) and hospitalized groups (n=8 and n=37). All patients were in the acute phase of infection (0–4 days post-symptom onset) and confirmed by RT-PCR to be infected with DENV-1 or DENV-2. Using single-cell RNA sequencing (scRNA-seq) combined with BCR and TCR sequencing, researchers analyzed frequencies of T and B cell subsets, gene expression, receptor clonal expansion, and frequencies of antigen-specific T cells. In addition, key results were validated using flow cytometry, including expression levels of molecules such as Ki-67, HLA-DR, PD-1, TIM-3, GzmB, GzmK, and IFN-γ.Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically characterizes adaptive immune differences between asymptomatic and hospitalized dengue patients, offering new immune markers for vaccine development. Future studies may explore whether these T and B cell features can serve as predictive indicators of vaccine efficacy, and whether vaccines targeting CD4+ TEMRA or enhancing Treg function could be developed. Additionally, the downregulation of type I IFN signaling and expansion of plasmablasts in hospitalized patients suggest that modulating IFN pathways or B cell responses might help control disease progression. Finally, while current approved dengue vaccines mainly induce neutralizing antibodies, this study supports the development of novel vaccines centered on T cell responses to enhance protective immunity.
Conclusion
Through single-cell multi-omics analysis, this study reveals differences in adaptive immune responses between asymptomatic and hospitalized dengue patients. Asymptomatic individuals exhibit expanded CD4+ TEMRA cells, enhanced Treg function, and upregulated type I IFN responses, whereas hospitalized patients display highly proliferative but hypofunctional CD8+ EM cells and pronounced expansion of IgG1+ plasmablasts. These findings provide novel candidate targets for dengue vaccine development and support the design of T cell-centered vaccines to enhance protective immune responses and mitigate antibody-dependent enhancement (ADE) effects. The study also highlights the potential importance of asymptomatic immune features in guiding future dengue vaccine development.
