Name
Role of Endogenous Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3 (APOBEC3) in clade IIb mpox virus evolution and host responses to mpox virus infection.
Presenter
Oluwaseyi Ajagbe, Vaccine for Infectious Disease Organization/ University of Saskatchewan
Co-Author(s)
Oluwaseyi Ajagbe1,2, Stephanie Saundh2, Reema Singh2, Angela Rasmussen1,2 1 Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, 2 Vaccine for Infectious Disease Organization, University of Saskatchewan
Abstract Category
Fighting & Responding
Abstract
Mpox virus (MPXV) clade IIb has circulated in West Africa since at least 2016 and later caused the 2022 global outbreak. Genomic analyses revealed about 46 single-nucleotide changes consistent with cytidine deamination by APOBEC3 enzymes, implicating human APOBEC3 activity rather than repeated zoonotic spillover. However, how endogenous APOBEC3s shape MPXV evolution in humans versus rodents, and how they influence host cellular responses, remain unclear. To compare host responses across species and cell types, we examined how MPXV clade IIb reprograms transcriptional networks in keratinocytes and in human (THP 1) and mouse (RAW 264.7) macrophages. We also assessed whether endogenous APOBEC3 expression in these cell lines contributes to MPXV mutation profiles. We analyzed viral nucleotide changes and host transcriptomes after MPXV infection in THP 1 and RAW 264.7 cells. Although MPXV replicated efficiently and produced infectious particles in both macrophage lines, no APOBEC3-associated mutations were detected in the virus genome. Transcriptomic profiling revealed cell-type-specific inflammatory and antiviral responses. Keratinocytes exhibited a pro-inflammatory phenotype, whereas macrophage responses were dominated by interferon-stimulated genes (ISGs). In THP 1 cells, APOBEC3B, APOBEC3C, and multiple ISGs were upregulated and predicted to be negatively regulated by the transcription factor ZNF750. Upregulation of the vitamin D receptor suggests a potential modulatory role for vitamin D in innate immunity. APOBEC3 expression was prominent in human but not mouse cells, supporting a role for human APOBEC3 enzymes in MPXV evolution and sustained human-to-human transmission rather than in direct rodent-to-human spillover.