Single-Nucleus and Spatial Transcriptomics Revealing Host Response Differences Triggered by Mutated Virus in Severe...

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Dengue virus (DENV) causes a spectrum of illness, from mild to severe, life-threatening disease.
• The molecular mechanisms driving severe dengue, especially in evolved DENV strains, remain incompletely understood.
• Host responses are critical in determining disease severity.

Purpose of the Study:

• To investigate the molecular mechanisms of severe dengue caused by an evolved DENV strain.
• To identify host factors and pathways involved in DENV-induced liver damage and pathogenicity.
• To analyze the host response to DENV in a murine model.

Main Methods:

• In silico molecular modeling of mutant DENV spatial structure.
• Single-nucleus and spatial RNA sequencing of liver tissues from infected and uninfected murine models.
• Serial passages of DENV-2 in Ifnra-/- mice to generate an evolved strain (N10).

Main Results:

• An evolved DENV-2 N10 strain exhibited enhanced replication and pathogenicity, causing severe liver damage in mice.
• Mutated DENV infection induced stronger responses in hepatocytes.
• The host factor Nrg4 and the NRG/ErbB pathway were identified as critical in severe DENV infection.

Conclusions:

• Evolved DENV strains can exhibit increased virulence and organ-specific pathogenicity.
• Host responses, including the NRG/ErbB signaling pathway, play a significant role in severe dengue.
• This study provides a framework for understanding host responses in severe dengue at the animal model level.