A novel single-cell communication framework combining multi-omics reveals neuro-viral pathogenesis in fish

Area of Science:

• Neuroscience
• Virology
• Molecular Biology

Background:

• The glutamate-glutamine cycle is vital for neuronal function but its role in teleost neurodegeneration is unclear.
• Red-spotted grouper nervous necrosis virus (RGNNV) causes significant neurological damage in fish.

Purpose of the Study:

• To investigate RGNNV-induced neurodegeneration using multi-omics approaches.
• To elucidate the role of the glutamate-glutamine cycle in RGNNV pathogenesis.
• To establish a cell communication framework for understanding viral susceptibility.

Main Methods:

• Multi-omics integration: transcriptomics, proteomics, single-cell transcriptomics, and ATAC-seq.
• Analysis of neuroactive ligand-receptor interactions and amino acid metabolism pathways.
• Investigation of cell communication networks and ferroptosis mechanisms.

Main Results:

• RGNNV disrupts glutamate-glutamine metabolism, affecting glutamate and GABA receptors.
• Altered signaling at the glulb locus correlates with increased viral susceptibility.
• Glutamate accumulation induces p53-mediated ferroptosis via glutathione and cysteine metabolism dysregulation.
• RGNNV triggers ferroptosis in grouper kidney cells through ferritinophagy.

Conclusions:

• Dysregulation of the glutamate-glutamine cycle is a key mechanism in RGNNV-induced neurodegeneration.
• The study provides a novel framework for analyzing cell communication in non-model organisms.
• Findings offer insights into nervous necrosis virus pathogenesis and potential therapeutic strategies.