Faculty Spotlight – Dr. Zsolt Toth

Award announcementDr. Zsolt Toth joined the Department of Oral Biology as an Assistant Professor, June 2016. He completed his MSc at the University of Szeged, in Hungary and his PhD at the Institute of Clinical and Molecular Virology of Friedrich-Alexander, University Erlangen-Nuremberg, Germany. Post-doctoral training began at the Salk Institute in La Jolla, California, while completing his work in the Department of Molecular Microbiology and Immunology at the University of Southern California (USC). In 2013, he became a Research Assistant Professor in that Department.

Dr. Toth has expansive training studying different aspects of the life cycles of various human viral pathogens.  As a graduate student, he studied how the viral mRNAs of Human Cytomegalovirus (HCMV, a major viral cause of congenital abnormalities) transported from the nucleus into the cytoplasm for translation, which is a critical step in HCMV replication. His work contributed to providing the first model of how the host mRNA export machinery is hijacked by HCMV to facilitate viral replication.

During his post-doc training, he began investigating the gene regulation of AIDS-related viral pathogens such as, HIV and KSHV, and at USC he studied the epigenetic regulation of the DNA genome of the oncogenic herpesvirus called Kaposi’s sarcoma-associated herpesvirus (KSHV).

Kaposi’s sarcoma-associated herpesvirus has a dual life cycle composed of a dormant state called latency and a lytic replication phase. At USC he established the analytical tools for the epigenetic analysis of the viral genome during latency and lytic reactivation, and characterized for the first time the dynamic binding of host epigenetic and transcription factors to the KSHV genome, and their connection to viral gene expression during latency and lytic reactivation. Most importantly, he found that the cellular Polycomb Repressive Complex 2 (PRC2), which regulates human genes involved in development is also responsible for the genome-wide silencing of KSHV genes thereby maintaining viral latency. Later, he discovered that the latent viral factor of KSHV called LANA is responsible for the recruitment of PRC2 to the KSHV genome, which serves as the basis of establishment of KSHV latency following primary infection. Collectively, studies at USC provided evidence that the modulation of the chromatin structure of KSHV DNA in infected cells plays a critical role in determining if KSHV maintains latency or enters lytic replication. His research, along with other’s research shows that epigenetic inhibitors that affect the chromatin of KSHV DNA could be used to control KSHV infection and ultimately KSHV-associated diseases. After his promotion to research assistant professor at USC, he began pursuing questions related to how viral chromatin controls the outcome of KSHV infection in the oral cavity.

At UF’s Department of Oral Biology, Dr. Toth has continued research of KSHV. One of the poorly understood aspects of KSHV infection is how KSHV can establish persistent infection in humans. The current model is that KSHV first infect epithelial cells in the oral cavity where it replicates, sheds into saliva and while also transmitted to B cells where KSHV establishes latency resulting in persistent infection of the host.

In immunocompromised patients, KSHV infection can result in oral cancer such as oral Kaposi’s sarcoma. Thus, the oral cavity plays an important role not only in dissemination of the KSHV but also virus-induced tumorigenesis. Oral epithelial cells are the first line of defense in the oral cavity by mounting rapid immune responses to block the spread of oral pathogens. Although several of KSHV genes encode immunoregulatory factors, it is still unknown how KSHV can avoid the viral infection-induced innate immune responses triggered in oral epithelial cells during infection. Due to the failure of the immune response in orally infected patients by KSHV, persistent infection is established[ in the host. Thus, one of the major efforts is in our lab to identify the critical viral and host factors and their role in innate immune evasion by KSHV in oral epithelial cells. To this end, my lab has been collaborating with Dr. Bernadett Papp, Research Assistant Professor at the Department of Oral Biology, who is a genomics expert, and Dr. Laurence M. Morel, an immunology expert from the Department of Pathology, Immunology and Laboratory Medicine. They are undertaking a multi-disciplinary approach to provide insights into how KSHV can evade host immune response during oral infection, which is the first step in the persistent infection of the host.

In addition, Dr. Toth’s lab also investigates the mechanisms of the establishment KSHV latency following primary infection and maintenance of KSHV latency in B cells. The research program integrates systems biology approaches with reverse viral genetics and structural-functional biochemical assays to interrogate the function of viral and host factors involved in the epigenetic and transcriptional regulation of the KSHV genome and host genes that are critical for KSHV infection, replication, and KSHV-induced cellular transformation, which can lead to the development of cancers.

The ultimate goal is to identify novel therapeutic targets for inhibiting KSHV infection and its associated diseases.