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EBV INFECTION OUTCOMES DETERMINED BY MONOCYTE AND TREG-DRIVEN IMMUNE DYNAMICS IN AN EX VIVO PBMC MODEL [RNA-Seq Mock]

ABSTRACT: Epstein-Barr virus (EBV) infects >95% of the adult population with diverse outcomes ranging from benign latency to cancers and autoimmune diseases. Immunological control of EBV infection is known to be an important determinant of EBV infection outcomes. However, species-specific viral tropism and limited infection models have impeded mechanistic insights into early host–immune control of EBV infection. Here, we use ex vivo infection of peripheral blood mononuclear cells (PBMCs), rather than routinely used B cell enriched culture systems, to study immune and viral dynamics during primary EBV infection. We combined bulk RNA sequencing, EBV transcript enrichment, and flow cytometry to characterize cellular responses across Days 1, 7–8, and 14 post-infection. Early infection triggered a monocyte-specific antiviral response marked by changes in the expression of genes associated with lipid metabolism (LIPA, lysosomal acid lipase) and chemotaxis (CCR1 and CCR2). Inhibitors of LIPA increased EBV titers during primary infection, indicating that LIPA is part of an early monocyte-driven antiviral response. At later timepoints post-infection, donor-dependent variability in lymphoblastoid cell line (LCL) outgrowth was associated with divergent immune states. Donors that failed to generate LCLs demonstrated increased frequencies of CD8+ T cells and reduced numbers of regulatory T cells (CD4⁺CD25⁺FOXP3⁺). EBV transcriptomics revealed that LCL-failed donors exhibited elevated early lytic gene expression but did not establish a type III latency program. Our findings suggest that individual variations in immune cell composition and gene expression may account for differences in the immune response to EBV. These findings define temporal immune and viral signatures that predict transformation outcome and highlight intact PBMCs as a tractable model to study EBV pathogenesis in a genetically diverse, human-specific context.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317338 | GEO | 2026/03/13

REPOSITORIES: GEO

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Project description:The Epstein-Barr virus (EBV) switches between latent and lytic phases in hosts that are important in developing related diseases. However, the underlying mechanism of how the viral latent-lytic switch is controlled and how EBV itself mediates this regulation remains largely unknown. This study identified the upregulated histone acetyl reader bromodomain-containing protein 7 (BRD7) during EBV latent infection. Based on the ChIP-sequencing of endogenous BRD7 in Burkitt lymphoma cells, we found that EBV drove BRD7 to regulate cellular and viral genomic loci, including the transcriptional activation of c-Myc, a recently reported regulator of EBV latency. Additionally, EBV-mediated BRD7 signals enriched around the FUSE site in chromosome 8, and the enhancer LOC108348026 in the lgH locus, which might activate the c-Myc alleles. Mechanically, EBV-encoded nuclear antigen 1 (EBNA1) bound and recruited BRD7 to colocalize at promotor regions of the related genes, thus serving as cofactors for the maintenance of viral latency. Moreover, the disruption of BRD7 decreased the c-Myc expression, induced the BZLF1 expression, and reactivated the lytic cycle. Our findings reveal the unique role of BRD7 hijacked by EBV in maintaining the viral latency state via chromatin remodeling. The study paved the way for understanding the new molecular mechanism of EBV-induced chromatin remodeling and latent-lytic switch regulation, providing novel therapeutic candidate targets for EBV persistent infection. With establishing persistent infection in most human hosts, EBV is usually at a latent infection state. How the viral latency is maintained in cells remains largely unknown. c-Myc was recently reported to act as a controller of the lytic switch, while whether and how EBV regulates it remains to be explored. Here, we identified that BRD7 is involved in controlling EBV latency. We found that EBV-mediated BRD7 was enriched in both the normal promoter regions and the translocation alleles of c-Myc, and the disruption of BRD7 decreased c-Myc expression to reactivate the lytic cycle. We also demonstrated that EBV-encoded EBNA1 bound to and regulated BRD7. Therefore, we reveal a novel mechanism by which EBV can regulate its infection state by hijacking host BRD7 to target c-Myc. Our findings will help future therapeutic intervention strategies of EBV infection and pathogenesis.

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EBV INFECTION OUTCOMES DETERMINED BY MONOCYTE AND TREG-DRIVEN IMMUNE DYNAMICS IN AN EX VIVO PBMC MODEL [RNA-Seq Mock]

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