Epigenetic Regulation of Host Membrane Protein-Coding Genes Facilitates African Swine Fever Virus Infection

Abstract African swine fever virus (ASFV) is a highly contagious pathogen that primarily affects domestic and wild pigs with specific tropism to porcine alveolar macrophages (PAMs), causing substantial economic losses in pig industry worldwide. Yet, host receptors and molecular mechanisms underlying the ASFV infection remain unknown, hindering the relevant vaccine development and precision breeding. Here, we present a comprehensive epigenetic atlas of ASFV-exposed PAMs by generating a total of 42 functional data at both bulk and single cell resolution. Suppressive expression regulation in ASFV-exposed cells showed that transcriptional activity of ARL4C was downregulated, leading to intracellular cholesterol accumulation for antiviral defense. In contrast, infection induced enhancer-promoter interactions in the host genome to boost transcriptional activity of membrane protein-coding genes, thereby contributing to macrophage activation. Moreover, actively infected macrophages (carrying viral DNA) exposed transcriptional induction of those genes. The following experimental validation highlighted CD244 as a potential host-receptor of ASFV, which was associated with host susceptibility. Our findings collectively provide novel insights into the molecular regulation of PAMs during ASFV infection, facilitating the identifion of new opportunities for vaccine development and precision breeding against ASFV infection.