Primary effusion lymphoma (PEL) and multicentric Castleman's disease arise in immunocompromised patients harboring human herpesvirus 8 (HHV8), the same oncogenic pathogen underlying Kaposi's sarcoma. Like EBV, HHV8 establishes lifelong infection by latently infecting B cells and expresses viral proteins capable of modulating B cell signaling and survival. Yet, in stark contrast to EBV, KSHV-infected cells are extremely rare in asymptomatic individuals, and efficient in vitro infection of B cells with KSHV has proven difficult. This suggests that KSHV may infect a small subset of B cells. The long-term goals of this project are to understand the biology and pathogenesis underlying primary B cell infection, examining the hypothesis that the target B cells may represent a unique environment allowing, in the setting of immunocompromise, cellular transformation. We hope to better understand the rules governing this process, with our initial goals being to: 1. Identify the subset(s) of B cells that support KSHV infection. We will utilize high throughput multimodal imaging technology to identify B cell targets of KSHV infection. Appreciating that infection may alter the B cell phenotype, we will confirm the identity of KSHV targets by isolating B cell subsets prior to infection and comparing the efficiency of infection in each subset. 2. Determine the effects of KSHV infection on B cell survival and function and identify candidate genes responsible for these changes. We will focus initial studies on KSHV-induced changes by examining proliferative capacity, survival and transformation ability in vitro. In parallel to these functional studies, we will use mini-microarrays focused on B cell activation pathways, followed by quantitative RT-PCR and/or western blot, to identify changes in cell signaling pathways that may be responsible for potential phenotypic changes.
Cancers and diseases of the immune cells in patients lead to significant morbidity and mortality throughout the world. Unfortunately, the rules governing how these diseases arise and how a healthy cell transforms into a malignant one remain unclear. By examining in the laboratory human viruses that can cause these types of cancers, it is our hope that we will gain insights into these rules, providing biomedical scientist the tools with which to develop better therapies and preventions.
|Hassman, Lynn M; Ellison, Thomas J; Kedes, Dean H (2011) KSHV infects a subset of human tonsillar B cells, driving proliferation and plasmablast differentiation. J Clin Invest 121:752-68|