Single-Cell Atlas of Spleen Remodeling Reveals Macrophage Subset-Driven ASFV Pathogenesis

Area of Science:

• Veterinary Virology
• Immunology
• Cellular Biology

Background:

• African swine fever virus (ASFV) poses a significant threat to global swine populations, causing devastating outbreaks.
• The precise cellular mechanisms underlying ASFV pathogenesis remain incompletely understood, hindering effective control strategies.

Purpose of the Study:

• To elucidate the cellular and molecular pathogenesis of ASFV infection in pigs at a high resolution.
• To identify specific host cell types and pathways involved in ASFV replication and immune response.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of pig spleen cells across four timepoints post-ASFV infection.
• Bioinformatic analysis of scRNA-seq data to identify cellular reservoirs, immune cell dynamics, and host-pathogen interactions.
• Analysis of viral gene expression and host transcriptomic pathways, including Netrin signaling.

Main Results:

• Macrophages identified as the primary cellular reservoir for ASFV, with distinct subsets exhibiting differential susceptibility and antiviral responses.
• ASFV infection induced lymphoid depletion and myeloid expansion, characterized by the emergence of a metabolically active 'SusceptibleMac' population and depletion of 'AntiviralMac' subsets.
• Viral gene E165R identified as a key regulator of viral replication, and disruption of host Netrin signaling pathways implicated in immune evasion.
• Pseudotime analysis revealed dynamic transitions between macrophage states during the course of infection.

Conclusions:

• ASFV pathogenesis involves complex interactions within specific macrophage subsets in the pig spleen.
• The study provides a detailed cellular atlas of ASFV infection, highlighting E165R and Netrin signaling as potential therapeutic targets.
• Understanding these subset-specific responses is crucial for developing interventions against ASFV outbreaks.