Human B cells are the primary targets of Epstein Barr virus (EBV) infection. In most cases EBV infection is asymptomatic because of a highly effective host immune response but some individuals develop self-limiting infectious mononucleosis, while others develop EBV-associated lymphoid or epithelial malignancies. The viral and immune factors that determine the outcome of infection are not understood. The EBV life cycle includes a lytic phase, culminating in the production of new viral particles, and a latent phase, during which the virus remains largely silent for the lifetime of the host in memory B cells. Thus, in healthy individuals there is a tightly orchestrated interplay between EBV and the host that allows the virus to persist. To promote viral persistence EBV has evolved a variety of strategies to modulate the host immune response including inhibition of immune cell function, blunting of apoptotic pathways, and interfering with antigen processing and presentation pathways. In this article we focus on mechanisms by which dysregulation of the host B cell, and immune modulation, by the virus can contribute to development of EBV+ B cell lymphomas.

The interrelationship between endogenous microbiota, the immune system, and tissue regeneration is an area of intense research due to its potential therapeutic applications. We investigated this relationship in Schmidtea mediterranea, a model organism capable of regenerating any and all of its adult tissues. Microbiome characterization revealed a high Bacteroidetes to Proteobacteria ratio in healthy animals. Perturbations eliciting an expansion of Proteobacteria coincided with ectopic lesions and tissue degeneration. The culture of these bacteria yielded a strain of Pseudomonas capable of inducing progressive tissue degeneration. RNAi screening uncovered a TAK1 innate immune signaling module underlying compromised tissue homeostasis and regeneration during infection. TAK1/MKK/p38 signaling mediated opposing regulation of apoptosis during infection versus normal tissue regeneration. Given the complex role of inflammation in either hindering or supporting reparative wound healing and regeneration, this invertebrate model provides a basis for dissecting the duality of evolutionarily conserved inflammatory signaling in complex, multi-organ adult tissue regeneration.DOI: http://dx.doi.org/10.7554/eLife.16793.001

Epstein-Barr Virus (EBV) is associated with potentially fatal lymphoproliferations such as post-transplant lymphoproliferative disorder (PTLD), a serious complication of transplantation. The viral mechanisms underlying the development and maintenance of EBV+ B cell lymphomas remain elusive but represent attractive therapeutic targets. EBV modulates the expression of host microRNAs (miRs), non-coding RNAs that regulate gene expression, to promote survival of EBV+ B cell lymphomas. Here, we examined how the primary oncogene of EBV, latent membrane protein 1 (LMP1), regulates host miRs using an established model of inducible LMP1 signaling. LMP1 derived from the B95.8 lab strain or PTLD induced expression of the oncogene miR-155. However, PTLD variant LMP1 lost the ability to upregulate the tumor suppressor miR-193. Small molecule inhibitors (SMI) of p38 MAPK, NF-κB, and PI3K p110α inhibited upregulation of miR-155 by B95.8 LMP1; no individual SMI significantly reduced upregulation of miR-155 by PTLD variant LMP1. miR-155 was significantly elevated in EBV+ B cell lymphoma cell lines and associated exosomes and inversely correlated with expression of the miR-155 target FOXO3a in cell lines. Finally, LMP1 reduced expression of FOXO3a, which was rescued by a PI3K p110α SMI. Our data indicate that tumor variant LMP1 differentially regulates host B cell miR expression, suggesting viral genotype as an important consideration for the treatment of EBV+ B cell lymphomas. Notably, we demonstrate a novel mechanism in which LMP1 supports the regulation of miR-155 and its target FOXO3a in B cells through activation of PI3K p110α. This mechanism expands on the previously established mechanisms by which LMP1 regulates miR-155 and FOXO3a and may represent both rational therapeutic targets and biomarkers for EBV+ B cell lymphomas.

No abstract

Post-Transplant Lymphoproliferative Disorder (PTLD) is a potentially fatal side effect of the immunosuppressive agents used to prevent allograft rejection. PTLD is associated with Epstein-Barr Virus (EBV) infection and can result in malignant B cell lymphoma. Latent membrane protein 1 (LMP1), a viral mimic of the B cell costimulatory protein CD40, is the major oncogene of EBV and can usurp host cell pathways to promote cell survival. LMP1 activates the Akt/PI3K signaling pathway to drive IL-10 production, which is essential for the autonomous proliferation of EBV+ B cell lymphomas. MicroRNAs are small, non-coding RNAs that post-transcriptionally regulate gene expression to control cellular events such as differentiation, proliferation, and cell survival. As aberrant expression of microRNAs is found in a variety of human malignancies, our goal was to determine if microRNAs participate in LMP1-induced IL-10 production in PTLD-derived cell lymphomas. To first establish that EBV infection can modulate host cell microRNA, we used Taqman microRNA qPCR arrays to detect the microRNA expression profiles of six B cell tumor lines derived from patients with PTLD, two B cell lines generated by infection with the B95.8 strain of EBV obtained from a patient with mononucleosis, and one EBV-negative B cell line. Expression data was then normalized internally and to the EBV-negative B cell line. Our analysis showed that compared to the EBV-negative B cell line, B cells infected with the benign B95.8 strain of EBV had the altered expression (2-fold) of 294 microRNAs while the PTLD-derived EBV+ B cell lines had the altered expression of 224 microRNAs. Twenty-eight microRNAs were altered in both cases of EBV infection. To examine the specific role of LMP1 in host cell microRNA expression, we used an inducible system of LMP1 activation and expressed different LMP1 molecules in an EBV negative B cell lymphoma line. Activation of the B95.8 form of LMP1 modulated 62 cellular microRNAs and 142 microRNAs were modulated by all five of the PTLD-derived LMP1 molecules. Notably, only 28 microRNAs were modulated by both benign and tumor LMP1. The microRNAs aberrantly regulated by either EBV infection or LMP1 activation were next analyzed with target prediction software for potential binding to the 3´UTR of IL-10.