Decoding dengue's neurological assault: insights from single-cell CNS analysis in an immunocompromised mouse model

Area of Science:

• Neuroscience
• Immunology
• Virology

Background:

• Dengue encephalitis is a severe neurological complication of dengue virus infection with increasing incidence.
• The underlying mechanisms and effective treatments for dengue encephalitis are not well understood.

Purpose of the Study:

• To construct a cellular atlas of dengue encephalitis using a mouse model.
• To identify the primary target cells of the dengue virus in the brain.
• To elucidate the role of immune cells, particularly CD8+ T cells, in the pathogenesis of dengue encephalitis.

Main Methods:

• Single-nucleus RNA sequencing was performed on brain tissues from a dengue-infected mouse model.
• Viral load and cytokine expression were quantified using RT-qPCR.
• Immunofluorescence and flow cytometry were used to identify target cells and assess CD8+ T cell cytotoxicity.
• In vivo experiments involved CD8+ T cell depletion and adoptive transfer.
• Axonal and synaptic integrity, as well as motor and sensory functions, were evaluated.

Main Results:

• Neurons, especially inhibitory GABAergic subtypes, were identified as the primary targets of the dengue virus.
• Immune cell infiltration, including CD8+ T cells, was observed in the brain, contributing to neurological damage.
• CD8+ T cells were found to infiltrate the brain, interact with neurons, and induce synaptic and axonal damage, leading to neurological dysfunction.

Conclusions:

• The study defined the cellular atlas of dengue encephalitis in a mouse model and identified specific neuronal targets of the dengue virus.
• The cytotoxic effects of CD8+ T cells were demonstrated, leading to neuronal apoptosis and neurological dysfunction.
• These findings provide a molecular and cellular framework for understanding dengue encephalitis and developing targeted therapies.