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Published on: June 28, 2024
Single-Cell Atlas of Spleen Remodeling Reveals Macrophage Subset-Driven ASFV Pathogenesis
Liyuan Wang1,2, Shouzhang Sun1,2,3, Lei Liu1,2,4
1Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518124, China.
Abstract:
African swine fever virus (ASFV) causes global swine outbreaks, but its cellular pathogenesis is poorly understood. Using single-cell RNA data from ASFV-infected pig spleens across four timepoints, we identified macrophages as the primary viral reservoir, with infection driving lymphoid depletion and myeloid expansion. We characterized four functionally distinct macrophage subsets, including a metabolically reprogrammed SusceptibleMac population serving as the major viral niche and an AntiviralMac subset rapidly depleted during infection. Viral gene expression analysis revealed E165R as a central hub in viral replication networks, while host transcriptomics uncovered disruption of Netrin signaling pathways that may facilitate immune evasion. Pseudotime analysis revealed dynamic macrophage state transitions during infection. These findings provide a high-resolution cellular atlas of ASFV pathogenesis, revealing macrophage subset-specific responses that shape disease outcomes and identifying potential targets for therapeutic intervention.
Insights
African swine fever virus (ASFV) infection primarily targets pig spleen macrophages, causing immune cell imbalances. Understanding these cellular dynamics reveals key viral mechanisms and potential therapeutic targets for ASFV.
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.
