Bhaduri Laboratory
Bridging the fields of Virology, Oncology, and Immunology, research in Bhaduri Laboratory focuses on understanding cancer development and progression by studying interactions between the opportunistic virus Epstein-Barr virus (EBV; a cancer-causing virus) and its host, the B cell, by investigating three main areas: 1) identifying mechanisms that determine susceptibility of EBV to lytic activation, a process important for herpesvirus persistence, 2) uncovering mechanisms that control the progress of the lytic phase, and 3) investigating how EBV subverts anti-pathogen and anti-cancer barriers to drive B cell proliferation and transformation.
McIntosh Laboratory
The McIntosh Laboratory employs molecular and cell biology, RNA-seq, capture-seq and proteomics to study gene expression networks associated with gammaherpesvirus infections, and to discover new viruses in human diseases of unknown etiology or emerging epidemiology, at the human animal or vector interface, and in the contexts of immunosuppression and cancer. Their goals are to develop new diagnostic markers, understand host factors contributing to disease, and identify targets for the development of vaccines, antibodies, and antiviral/anticancer therapeutics.
Gammaherpesviruses
Like other herpesviruses, Gammaherpesviruses Epstein-Barr virus (EBV; Human herpesvirus 4) and Kaposi’s sarcoma-associated herpesvirus (KSHV; Human herpesvirus 8) have a life cycle consisting of a lytic or productive phase and a latent or quiescent phase. Regulation of these phases is central to immune evasion, transmission, and pathogenesis in acute and chronic diseases as well as in associated lymphoproliferative diseases (LPD), lymphomas, and epithelial cell cancers. Both viruses are known to persist latently in B lymphocytes with periodic lytic (re)activation producing virus particles that can infect new B cells, expanding the pool of latently infected B cells or epithelial cells, and supporting transmission to new hosts. This contributes to high prevalence rates of up to 60% for KSHV among distinct populations and a near ubiquitous presence of EBV with greater than 95% prevalence worldwide.
While EBV and KSHV generally persist as asymptomatic infections in immunocompetent individuals, EBV can cause infectious mononucleosis, frequently upon primary infection of adolescents, and both are causal to a number of lymphomas and cancers. EBV causes endemic African Burkitt lymphoma (BL) and nasopharyngeal cell carcinoma while also contributing to Hodgkin lymphoma and some gastric cancers. More frequently, in immunocompromised individuals and transplant recipients, EBV causes diffuse large B cell lymphoma and B cell LPD, as well as more rarely T and natural killer (NK) cell lymphomas. EBV also contributes to autoimmune diseases such as multiple sclerosis. KSHV causes Kaposi’s sarcoma, an immunosuppression-associated multifocal cancer derived from vascular endothelial cells. KSHV, combined with severe immunosuppression, is also associated with primary effusion B cell lymphoma (PEL), HHV8-associated germinotropic LPD, and multicentric Castleman disease.
EBV and KSHV have linear dsDNA genomes, ca. 170 kb and 140 kb in size, respectively, with nearly 100 genes each. Most of the genes encode proteins or RNA that function during lytic production of virus. During latency however, the multicopy nuclear localized viral genomes circularize as episomes with a mere few protein-coding genes, and/or microRNA (miRNA) and long non-coding RNA (lncRNA) maintaining expression to promote cell survival, proliferation, and viral latency. This silencing is critical to immune evasion and viral persistence.