Induction of Interferon-Stimulated Genes on the IL-4 Response Axis by Epstein-Barr Virus Infected Human B Cells; Relevance to Cellular Transformation

Abstract

Epstein-Barr virus (EBV) is an oncogenic virus that is associated with the pathogenesis of several human lymphoid malignancies, including Hodgkin's lymphoma. Infection of normal resting B cells with EBV results in activation to lymphoblasts that are phenotypically similar to those generated by physiological stimulation with CD40L plus IL-4. One important difference is that infection leads to the establishment of permanently growing lymphoblastoid cell lines, whereas CD40L/IL-4 blasts have finite proliferation lifespans. To identify early events which might later determine why EBV infected blasts go on to establish transformed cell lines, we performed global transcriptome analyses on resting B cells and on EBV and CD40L/IL-4 blasts after 7 days culture. As anticipated there was considerable overlap in the transcriptomes of the two types of lymphoblasts when compared to the original resting B cells, reflecting common changes associated with lymphocyte activation and proliferation. Of interest to us was a subset of 255 genes that were differentially expressed between EBV and CD40L/IL-4 blasts. Genes which were more highly expressed in EBV blasts were substantially and significantly enriched for a set of interferon-stimulated genes which on further in silico analyses were found to be repressed by IL-4 in other cell contexts and to be up-regulated in micro-dissected malignant cells from Hodgkin's lymphoma biopsies when compared to their normal germinal center cell counterparts. We hypothesized that EBV and IL-4 were targeting and discordantly regulating a common set of genes. This was supported experimentally in our B cell model where IL-4 stimulation partially reversed transcriptional changes which follow EBV infection and it impaired the efficiency of EBV-induced B cell transformation. Taken together, these data suggest that the discordant regulation of interferon and IL-4 pathway genes by EBV that occurs early following infection of B cells has relevance to the development or maintenance of an EBV-associated malignancy.

Dysregulation of Dual-Specificity Phosphatases by Epstein-Barr Virus LMP1 and Its Impact on Lymphoblastoid Cell Line Survival

“…2C and D). Our results were consistent with data reported previously from the laboratory of M. Rowe (17). Our results demonstrated that anti-CD40/IL-4 can reduce expression of DUSP6, which is consistent with the findings obtained by Rowe et al using array and RT-Q-PCR analysis; furthermore, they found that only IL-4 was able to attenuate this downregulation.…”

Shared Molecular Signatures Across Neurodegenerative Diseases and Herpes Virus Infections Highlights Potential Mechanisms for Maladaptive Innate Immune Responses

“…We recalculated fold changes for AD and PD, and results are comparable with previous studies 18,19 . Based on the filtering criteria described in the Methods section, six datasets were selected (Table 1): GSE636063 (132 whole blood samples from healthy vs 135 AD patients 18 ), GSE99039 (whole blood samples from 232 healthy vs 204 PD patients 19 ), GSE81246 (peripheral blood mononuclear cells (PBMC) from 24 patients with latent CMV infection vs 10 patients with active disease 20 ), GSE20200 21 and GSE45829 22 (7 B cell independent samples vs 7 EBV infected samples), and GSE40396 (22 whole blood samples from seronegative patients vs 10 patients seropositive for HHV6 with fever 23 ). Table S1 summarizes all retrieved datasets along with the reasons for their inclusion or exclusion from our analyses.…”

Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity

“…Further, among the 80 differentially expressed genes we detect, many of them represent classic host genes whose expression is modulated by EBV. Genes whose expression is concordantly activated by EBV include CD44 78 , TNFAIP2 79 , MX1 80 , and IFI44 81 ; genes with lowered expression include VAV3 82 and CD99 83 .…”