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Chronic Active Epstein-Barr Virus Disease Originates from Infected Hematopoietic Stem Cells

ABSTRACT: Chronic active Epstein-Barr Virus (EBV) disease (CAEBV) is lethal syndrome due to persistent EBV infection. When diagnosed as CAEBV, EBV infection was observed in multiple hematopoietic lineages, but the etiology of CAEBV is still elusive. Bone marrow and peripheral cells derived from five CAEBV patients, one EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) patient, and two healthy controls were analyzed. Multiple assays were applied to identify and characterize EBV-infected cells, including quantitative PCR (qPCR), PrimeFlow and single-cell RNA-sequencing (scRNA-seq). Based on scRNA-seq data, alterations in gene expression of particular cell types were analyzed between CAEBV patients and controls, and between infected and uninfected cells. One CAEBV patient was treated with allogeneic hematopoietic stem cell transplantation (HSCT), and the samples derived from this patient were analyzed again six month after HSCT. EBV infected the full spectrum of the hematopoietic system including both lymphoid and myeloid lineages, so as hematopoietic stem cells (HSCs) in the CAEBV patients. EBV-infected HSCs exhibited a higher differentiation rate towards downstream lineages, and the EBV infection had an impact on both the innate and adaptive immunity, resulting in inflammatory symptoms. EBV infected cells were thoroughly removed from the hematopoietic system after HSCT. Taken together, multiple lines of evidence presented in this study suggest that CAEBV disease originates from the infected hematopoietic stem cells.

ORGANISM(S): human gammaherpesvirus 4 Homo sapiens

PROVIDER: GSE231946 | GEO | 2023/10/24

REPOSITORIES: GEO

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Project description:The oral cavity is the persistent reservoir for EBV with lifelong infection of resident epithelial and B cells. Infection of these cell types results in distinct EBV gene expression patterns that are regulated by epigenetic modifications involving DNA methylation and chromatin structure. Such regulation of EBV gene expression relies on viral manipulation of the host epigenetic machinery that may inadvertently result in long-lasting, oncogenic host epigenetic reprogramming. To test this hypothesis in the context of EBV infection of epithelial cells, we established a transient infection model to identify the epigenetic consequences after EBV infection of immortalized normal oral keratinocytes and subsequent viral loss. With mounting evidence that EBV can induce epigenetic alterations, we developed a transient infection model where a clonal derivative (designated cl1) from a human telomerase immortalized normal oral keratinocyte (NOK) cell line was infected with a recombinant Akata EBV carrying neomycin resistance and GfP cassette in place of the BXLF1 open reading frame. Infected cells were passaged ten times, and then selection pressure was removed for an additional ten passages to allow for viral loss. Three transiently-infected EBV-negative clones were identified by single cell cloning (designated cl1, cl3, cl4). Uninfected parental clone and cells transfected with PTRUF5 plasmid were passaged alongside the transiently-infected clones. The transcription profiles were analyzed using Affymetrix microarray U133Plus2.0 arrays in duplicate. NOK cells were single cell cloned (designated as cl1) and EBV infected by co-culture with a recombinant Akata EBV strain carrying neomcycin resistance and GFP expression cassette in place of EBV BXLF1. Cells were selected with 350 ug/ml G418. As a selection control, cells were transfected a plasmid carrying a neomycin resistance cassette. Cells were passaged 10 times with G418, followed by removal of selection pressure. After an additional 10 passages, cells were single cell cloned and the presence of EBV was determined by various methods. Three clones were identified as being EBV negative and said to be transiently infected. Uninfected parental and vector transfected cells were passaged in the same manner and also single cell cloned.

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Chronic Active Epstein-Barr Virus Disease Originates from Infected Hematopoietic Stem Cells

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