Periodontal bacteria enhance oral KSHV pathogenesis and Kaposi's Sarcoma development in HIV + patients

牙周细菌增强 HIV 患者口腔 KSHV 发病机制和卡波西肉瘤的发展

• 批准号: 10400690
• 负责人: James Craig Forrest
• 金额: $ 37.24万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400690
• 关键词: AIDS/HIV problem; Address; Anti-HIV Therapy; Antibiotics; Antioxidants; Bacteria; Biological; Cell Culture Techniques; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Common Neoplasm; Conditioned Culture Media; Cyclin D1; Data; Development; Environment; Etiology; HIV; HIV Infections; Heparan Sulfate Proteoglycan; Herpesviridae Infections; High Prevalence; Human; Human Herpesvirus 8; Immunocompromised Host; Immunosuppression; Incidence; Infection; Inflammation; Kaposi Sarcoma; Link; Lipopolysaccharides; Lytic; Maintenance; Methods; MicroRNAs; Molecular; Morbidity - disease rate; Mouth Neoplasms; Oncogenic Viruses; Oral; Oral cavity; Palate Kaposi' s Sarcoma; Pathogenesis; Patients; Pattern; Periodontal Diseases; Plasma; Porphyromonas gingivalis; Prevention; Preventive; Production; Publishing; Reactive Oxygen Species; Regulation; Risk; Role; Saliva; Salivary; Sampling; Staphylococcus aureus; Structure; TLR2 gene; Time; Tumor Tissue; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Latency; Virus Shedding; base; clinical development; clinically relevant; co-infection; cohort; infection rate; innovation; insight; latent gene expression; lipoteichoic acid; mortality; novel; oral fibroblast; oral microbiome; pathogen; pathogenic bacteria; prevent; protein expression; reactivation from latency; receptor; therapeutic target; transmission process; tumor; tumorigenesis; virus related cancer

PROJECT ABSTRACT Kaposi's sarcoma (KS) remains the most common tumor arising in patients with HIV/AIDS, and involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. HIV infection incurs an increased risk for periodontal diseases and oral carriage from a variety of pathogenic bacteria. However, whether interactions involving periodontal bacteria and oncogenic viruses in the local environment facilitate replication or maintenance of these viruses in the oral cavity remains largely unknown. Our published and preliminary data indicate that incubation of human primary oral cells with two prototypical pathogen-associated molecular patterns (PAMPs) produced by prominent periodontal bacteria—lipoteichoic acid (LTA) from Staphylococcus aureus (Sa) and lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg)—increases initial viral entry and subsequent latent gene expression during de novo KSHV infection. Moreover, LTA and LPS up-regulate one of cellular receptors for KSHV entry, Heparan sulfate proteoglycan (HSPG) and increase reactive oxygen species (ROS) production as co-factor contributed to KSHV infection. Additionally, we found that conditioned medium from Sa and Pg culture or bacterial PAMPs induced viral lytic reactivation from latently infected oral cells through regulation of viral microRNAs expression, promoting virus dissemination. For clinical relevance, we found a high infection and co-infection rate of Sa, Pg and KSHV in the oral cavity of our cohort of HIV+ patients, and found higher levels of salivary ROS, host antioxidant factors and bacterial LTA/LPS from HIV+/KSHV+ patients than those HIV+/KSHV- ones. Based on these data, we hypothesize that periodontal bacteria or their PAMPs may facilitate initial KSHV infection, replication and dissemination in the oral cavity of HIV+ patients through multiple host and viral factors, and ultimately promote oral KS development. To address this hypothesis, we propose the following specific aims including both clinical and basic studies: 1) Determine the clinical relevance and correlations between host salivary antioxidant factors, specific bacterial carriage/PAMPs levels, and KSHV oral shedding in HIV+ patients. 2) Identify the mechanisms through which periodontal bacteria or their PAMPs facilitate KSHV initial infection and viral lytic reactivation, two important steps necessary for KS development. Through these efforts, we can better understand how pathogens co-infection can promote virus-associated cancer development in oral unique niche of immunocompromised patients. Our results will also provide the framework for the development of clinical trials evaluating the strategies interfering with host-bacteria-virus interaction (e.g. specific antibiotics, targeting TLRs-ROS axis or viral microRNAs synthesis) for their abilities to reduce or prevent oral KSHV infection and KS progression in HIV+ patients.

项目摘要 Kaposi的肉瘤（KS）仍然是艾滋病毒/艾滋病患者产生的最常见肿瘤，并且参与 口腔代表该肿瘤最常见的临床表现之一。艾滋病毒感染引起 从多种致病细菌中增加了牙周疾病和口服运输的风险。然而， 当地环境中涉及牙周细菌和致癌病毒的相互作用是否有助于 这些病毒在口腔中的复制或维持仍然很大未知。我们出版的 初步数据表明，将人类原代细胞与两个原型病原体相关的 由突出的牙周细菌产生的分子模式（PAMP） - 脂肪甲酸（LTA） 来自牙龈卟啉单胞菌（PG）的金黄色葡萄球菌（SA）和脂多糖（LPS） - 感染 初始病毒输入和随后的潜在基因表达在新的KSHV感染期间。而且，LTA和 LPS上调了KSHV进入的细胞接收器之一，硫酸乙酰肝素蛋白聚糖（HSPG）并增加 活性氧（ROS）作为共同因素的产生导致KSHV感染。另外，我们发现 从SA和PG培养或细菌PAMPS引起病毒裂解再激活的条件培养基。 通过调节病毒microRNA的表达来延伸感染口腔细胞，从而促进病毒传播。为了 临床相关性，我们发现在我们的口腔中，SA，PG和KSHV的高感染率和共同感染率很高 艾滋病毒+患者队列，发现唾液ROS的水平较高，宿主抗氧化因子和细菌 来自HIV+/KSHV+患者的LTA/LPS比HIV+/KSHV-患者。基于这些数据，我们假设 牙周细菌或其大弹药可能促进初始KSHV感染，复制和传播 在HIV+患者的口腔中，通过多种宿主和病毒因素，最终促进口头 KS开发。为了解决这一假设，我们提出了以下特定目标，包括两个临床 和基础研究：1）确定宿主唾液抗氧化剂之间的临床相关性和相关性 HIV+患者的因素，特定的细菌托架/弹药水平和KSHV口腔脱落。 2）确定 牙周细菌或其助长的机制可促进KSHV初始感染和病毒裂解 重新激活，KS开发所需的两个重要步骤。通过这些努力，我们可以更好 了解病原体共同感染如何促进与病毒相关的癌症发展 免疫功能低下的患者。我们的结果还将为开发临床提供框架 评估与宿主 - 细菌病毒相互作用相互作用的策略的试验（例如，特定的抗生素，靶向 TLRS-ROS轴或病毒microRNAS合成），以减少或预防口服KSHV感染和 HIV+患者的KS进展。