Human cytomegalovirus (HCMV) is among the most common causes of oral diseases associated with AIDS patients. Persistent and latent infections of HCMV are common in oral cavity. Oral reservoirs of HCMV play an important role in viral transmission and pathogenesis. For example, HCMV infection in oral mucosa, which engages controlled but persistent production and shedding of infectious particles without apparent onset of oral diseases, represents the major source for viral transmission. Understanding the mechanism of HCMV infection in oral mucosa as well as other parts of the oral cavity and eliminating HCMV from its oral reservoirs are central to the prevention of HCMV transmission and its associated diseases. The objective of the proposed research is to study HCMV persistent infection in oral mucosa. We have recently showed that HCMV infection can engage a restrained and controlled production of viral progeny and exhibit no significant cytopathic effect in cultured oral cells and tissues, suggesting that these cultured cells and tissues can be used as the models to study HCMV productive and persistent infections in oral mucosa. Furthermore, preliminary studies have suggested that specific viral proteins block apoptosis and modulate viral gene transcription, leading to the protection and survival of the infected cells and the establishment of controlled but persistent infection in oral mucosa. In the initial part of th proposed study, we will screen a collection of HCMV mutants with deletion of a single viral open reading frame (ORF) to identify viral determinants important for viral productive and persistent infection in oral mucosa. Experiments will then be carried out to study the roles of the identified viral factors in supporting viral infection in oral cells. Furthermore, experiments will also be carried out to investigate how the viral determinants modulate viral gene transcription and inhibit viral-induced apoptosis by interacting with the host transcription machinery and the components of the cellular apoptotic processes in order to achieve successful HCMV persistent infection in oral cavity. These studies will lead to the identification of viral determinants important for vira infection in oral mucosa. Our results will also provide insight into the mechanism of HCMV productive and persistent infection in oral mucosa and facilitate the development of novel strategies for eliminating HCMV infection from its oral reservoirs and for prevention of the transmission and infection of HCMV in oral cavity.

Public Health Relevance

The objective of the proposed research is to study the persistent 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 eliminating HCMV from its oral reservoirs and 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 #
5R01DE025462-04
Application #
9477721
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Lunsford, Dwayne
Project Start
2015-07-10
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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
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, 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
Gu, Hongwei; Zhao, Chihao; Zhang, Tianfu et al. (2017) Salmonella produce microRNA-like RNA fragment Sal-1 in the infected cells to facilitate intracellular survival. Sci Rep 7:2392
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

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