ASFV early infection dynamically remodels host chromatin architecture to evade immune responses

Abstract

African swine fever (ASF), a lethal and highly contagious viral disease, continues to inflict substantial economic losses on the global swine industry. The etiological agent African swine fever virus (ASFV), a member of the nucleocytoplasmic large DNA viruses (NCLDV) family, primarily targets macrophages. ASFV evades the host immune system by modifying host gene expression to manipulate programmed cell death and immune responses. ASFV infection can epigenetically modulate host gene expression through alterations in chromatin conformation. The impact of ASFV on the nucleus is particularly evident during early infection, underscoring the critical need to investigate this pivotal phase. Through integrative multi-omics analysis combining time-course RNA-seq, CUT&Tag, IP-MS, and Hi-C we systematically characterized dynamic alterations in the host transcriptome, RNA polymerase II (RNAP II) activity, and three-dimensional genome architecture at 2, 4, and 6 h post-infection using both a virulent ASFV strain and its live-attenuated derivative. Our findings reveal that early ASFV infection significantly altered the three-dimensional architecture of host chromatin, characterized by increased heterochromatinization, repositioning of topologically associating domain (TAD) boundaries, and altered chromatin interaction intensities and spatial distances. We also observed interactions between viral DNA and host chromatin. The host antiviral transcriptional program was indistinguishable between virulent and attenuated strains despite the loss of MGF-encoded factors in the attenuated virus, demonstrating that early innate immune activation is independent of these virulence determinants. RNAP II protein levels showed no significant change, but its genomic occupancy was redistributed and its interactome remodeled, with core polymerase subunits and Mediator components enriched while sequence-specific transcription factors were depleted. These coordinated changes reveal extensive host chromatin and transcriptional remodeling during early ASFV infection, suggesting that chromatin reorganization may contribute to ASFV immune evasion.