Oral infection represents an important route of human cytomegalovirus (HCMV) transmission. HCMV infection is also among the most common causes of oral diseases associated with AIDS patients. Understanding the mechanism of HCMV infection in oral mucosa as well as other parts of the oral cavity will provide insight into developing new drugs and novel strategies for treatment and prevention of HCMV-associated oral diseases. The objective of the proposed research is to study HCMV chromatin modifications and their roles in viral infection in oral mucosa. Recent studies in our laboratory have shown that epigenomic modifications, including histone tail changes by methylation, have been found in HCMV chromatin in human primary oral cell and tissue cultures. Furthermore, preliminary studies have suggested that specific viral proteins affect the epigenetic modifications of viral chromatin, and that some of these modifications specifically modulate the expression of viral gene expression required for HCMV productive infection. In the initial part of the proposed study, we will screen a collection of HCMV mutants with deletion of a single viral open reading frame (ORF) to isolate mutants that exhibit altered viral chromatin modifications and to identify viral determinants important for specific modifications of HCMV chromatin in oral mucosa. Experiments will then be carried out to study the roles of the identified modifications of viral chromatin in regulating viral gene transcription and supporting viral infection in oral cells. Furthermore, experiments will also be carried out to investigate how the viral determinants modulate specific HCMV chromatin modifications by interacting with the epigenetic remodeling complexes in order to facilitate HCMV infection in oral cavity. These studies will lead to the identification of viral determinants important for HCMV chromatin modifications and for viral infection in oral mucosa. Furthermore, our studies will investigate how HCMV replicates in oral mucosa and how HCMV-encoded determinants function to modulate HCMV chromatin modifications and support viral infection in oral mucosa. Our results will provide insight into the mechanism of HCMV infection in oral mucosa and facilitate the development of novel strategies for treatment and prevention of the transmission as well as infection of HCMV in oral cavity.

Public Health Relevance

The objective of the proposed research is to study the roles of viral chromatin modifications in oral infections of human cytomegalovirus, a leading cause of viral congenital infections and one of the most common opportunistic pathogens encountered in AIDS patients. Our study will facilitate the development of novel approaches and therapeutic agents for the prevention and treatment of HCMV infections in oral cavity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE023935-02
Application #
8734379
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2013-09-15
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Type
Schools of Public Health
DUNS #
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Feng, Linyuan; Sheng, Jingxue; Vu, Gia-Phong et al. (2018) Human cytomegalovirus UL23 inhibits transcription of interferon-? stimulated genes and blocks antiviral interferon-? responses by interacting with human N-myc interactor protein. PLoS Pathog 14:e1006867
Li, Wei; Liu, Yujun; Wang, Yuanyuan et al. (2018) Engineered RNase P Ribozymes Effectively Inhibit the Infection of Murine Cytomegalovirus in Animals. Theranostics 8:5634-5644
Zhu, Dihan; Pan, Chaoyun; Sheng, Jingxue et al. (2018) Human cytomegalovirus reprogrammes haematopoietic progenitor cells into immunosuppressive monocytes to achieve latency. Nat Microbiol 3:503-513
Chen, Yuan-Chuan; Sheng, Jingxue; Trang, Phong et al. (2018) Potential Application of the CRISPR/Cas9 System against Herpesvirus Infections. Viruses 10:
Li, Xihan; Fu, Zheng; Liang, Hongwei et al. (2018) H5N1 influenza virus-specific miRNA-like small RNA increases cytokine production and mouse mortality via targeting poly(rC)-binding protein 2. Cell Res 28:157-171
Sun, Xu; Chen, Weijie; He, Lingling et al. (2017) Inhibition of human cytomegalovirus immediate early gene expression and growth by a novel RNase P ribozyme variant. PLoS One 12:e0186791
Francis, Stephen Starko; Wallace, Amelia D; Wendt, George A et al. (2017) In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia. Blood 129:1680-1684
Chen, Jun; Xia, Sisi; Yang, Xiangmin et al. (2017) Human Cytomegalovirus Encoded miR-US25-1-5p Attenuates CD147/EMMPRIN-Mediated Early Antiviral Response. Viruses 9:
Zhao, Chihao; Zhou, Zhen; Zhang, Tianfu et al. (2017) Salmonella small RNA fragment Sal-1 facilitates bacterial survival in infected cells via suppressing iNOS induction in a microRNA manner. Sci Rep 7:16979
Li, Wei; Sheng, Jingxue; Xu, Mengqiong et al. (2017) Inhibition of Murine Cytomegalovirus Infection in Animals by RNase P-Associated External Guide Sequences. Mol Ther Nucleic Acids 9:322-332

Showing the most recent 10 out of 26 publications