Viral infections can cause diverse diseases ranging from transient effects to serious lifelong defects, developmental delays and even cancer. The primary site of infection is often the oral cavity, which has the potential to cause lasting alterations in the infected and neighboring cells. Herpesviruses, such as our model DNA virus, the Kaposi's sarcoma-associated herpesvirus (KSHV) can replicate in oral epithelial cells, which allows the spreading of the virus in the host and can promote the transmission of the virus from person to person. We have performed a genomewide gene expression time-course analysis in human primary gingival epithelial cells infected by KSHV. Our analysis revealed that subset of the host genes are deregulated during infections in the direction, which correlate with their expression level associated with poor prognosis and worsening degree of dysplasia in the oral cavity. We found a rapid induction of two members of the Forkhead family of transcriptional factors (TFs) and also identified that a large fraction of the deregulated genes could be targets of the rapidly induced Forkhead TFs. Previous studies have shown that deregulated expression of Forkhead TFs can cause head and mouth deformations whereas their high levels can be associated with subtypes of cancer. The function of these Forkhead TFs has been previously described in various contexts such as during developmental decisions and tumorigenesis. Despite their clear significance, their involvement and apparent deregulations during viral infection in the oral cavity has not been demonstrated yet. Based on our preliminary data we propose that the rapidly induced Forkhead TFs can play a critical role in the regulation of herpesviral infections in oral epithelial cells. To reveal the role of Forkhead TFs in KSHV infection, we will identify their genomic targets, its associated cellular factors and their role in Forkhead TF-mediated transcription repression. Lastly, we will perform a comprehensive transcriptome analysis in primary oral epithelial cells following infection with different herpesviruses. Our goal is to identify the common host genes that are deregulated by alpha-, beta- and gamma-herpesviruses, which can be critical in the regulation of oral herpesvirus infection and future disease development. By better understanding of the common host responses triggered by distinct herpesviruses in oral epithelial cells, we can identify new therapeutic targets to develop antiviral treatments in order to inhibit viral replications and their associated diseases in the oral cavity.

Public Health Relevance

The primary site of viral infections is often the oral cavity, which can acquire long lasting detrimental alterations over time. We use genomics approaches to create an unbiased picture of the rapid stepwise global events that support the lytic replication of herpesviruses in newly infected oral cells. The goal of this proposal is to determine what are the conserved regulatory events during oral infections by all three family members of herpesviruses, which knowledge has the potential to significantly transform our understanding of the events determining the outcome of viral infections and oral diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Small Research Grants (R03)
Project #
5R03DE028029-02
Application #
9771442
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Melillo, Amanda A
Project Start
2018-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Florida
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611