Persistent infection of human cytomegalovirus in oral mucosa

口腔粘膜持续感染人巨细胞病毒

• 批准号: 9257373
• 负责人: Fenyong Liu
• 金额: $ 45.38万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-10 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257373
• 关键词: AIDS-Related Disorder; Acquired Immunodeficiency Syndrome; Animals; Antiviral Agents; Apoptosis; Apoptotic; Cells; Cessation of life; Collection; Cultured Cells; Cytomegalovirus; Development; Disease; Exhibits; Gene Deletion; Genetic Transcription; Growth; Human; Immediate-Early Genes; In Vitro; Infection; Laboratories; Modeling; Mouth Diseases; Myelogenous; Open Reading Frames; Oral; Oral cavity; Oral mucous membrane structure; Pathogenesis; Pathway interactions; Patients; Play; Prevention; Primary Infection; Process; Production; Proteins; Reporting; Research; Role; Salivary Glands; Small Interfering RNA; Source; Stem cells; Study models; System; Therapeutic Agents; Tissue Model; Tissues; Transcript; Viral; Viral Genes; Viral Pathogenesis; Viral Proteins; Virus Diseases; Virus Replication; congenital infection; experimental study; insight; keratinocyte; latent infection; monocyte; mutant; novel strategies; novel therapeutics; oral infection; oral tissue; overexpression; particle; pathogen; public health relevance; tissue/cell culture; transmission process; viral transmission

 DESCRIPTION (provided by applicant): 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.

 描述（由申请人提供）：人巨细胞病毒（HCMV）是与艾滋病患者相关的口腔疾病的最常见原因之一。HCMV在口腔中的持续性和潜伏性感染较为常见。口腔宿主在HCMV的传播和发病中起重要作用。例如，口腔粘膜中的HCMV感染是病毒传播的主要来源，其涉及感染性颗粒的受控但持续的产生和脱落，而没有明显的口腔疾病发作。了解口腔粘膜以及口腔其他部位的HCMV感染机制并从其口腔储库中清除HCMV是预防HCMV传播及其相关疾病的核心。 本研究的目的是研究口腔粘膜中HCMV的持续感染。我们最近的研究表明，HCMV感染可以在体外培养的口腔粘膜细胞和组织中抑制和控制病毒子代的产生，并且没有表现出明显的细胞病变效应，这表明这些培养的细胞和组织可以用作研究口腔粘膜中HCMV产生性和持续性感染的模型。此外，初步研究表明，特定的病毒蛋白质阻断细胞凋亡并调节病毒基因转录，导致受感染细胞的保护和存活， 口腔粘膜建立可控制但持续的感染。 在本研究的初始阶段，我们将筛选一组缺失单个病毒开放阅读框（ORF）的HCMV突变体，以鉴定对口腔粘膜病毒产生性和持续性感染重要的病毒决定簇。然后将进行实验以研究所确定的 支持口腔细胞中病毒感染的病毒因子。此外，还将进行实验以研究病毒决定簇如何调节病毒基因转录和抑制病毒基因转录。 病毒通过与宿主转录机制和细胞凋亡过程的组分相互作用诱导细胞凋亡，以实现口腔中HCMV的成功持续感染。这些研究将导致确定病毒的决定因素，重要的病毒感染口腔粘膜。我们的研究结果也将有助于深入了解HCMV在口腔粘膜中产生和持续感染的机制，并促进新的策略的发展，以消除HCMV感染的口腔水库和预防HCMV在口腔中的传播和感染。