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: 10613370
• 负责人: James Craig Forrest
• 金额: $ 32.46万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613370
• 关键词: 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; HIV/AIDS; Heparan Sulfate Proteoglycan; Herpesviridae Infections; High Prevalence; Human; Human Herpesvirus 8; Immunocompromised Host; Immunosuppression; Incidence; Incubated; 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; clinical development; clinically relevant; co-infection; cofactor; 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 卡波西肉瘤（KS）仍然是艾滋病毒/艾滋病患者中最常见的肿瘤，并且涉及 口腔是这种肿瘤最常见的临床表现之一。 牙周病和口腔携带多种致病菌的风险增加。 当地环境中涉及牙周细菌和致癌病毒的相互作用是否促进 这些病毒在口腔中的复制或维持仍然很大程度上未知。 初步数据表明，将人类原代口腔细胞与两种典型病原体相关的细胞一起孵育 由著名牙周细菌——脂磷壁酸（LTA）产生的分子模式（PAMP） 金黄色葡萄球菌 (Sa) 和牙龈卟啉单胞菌 (Pg) 的脂多糖 (LPS) — 增加 此外，LTA 和新 KSHV 感染期间的初始病毒进入和随后的潜伏基因表达。 LPS 上调 KSHV 进入细胞受体之一硫酸乙酰肝素蛋白聚糖 (HSPG) 并增加 此外，我们发现活性氧 (ROS) 的产生是 KSHV 感染的辅助因子。 Sa 和 Pg 培养物的条件培养基或细菌 PAMP 诱导病毒裂解再激活 通过调节病毒microRNA的表达来抑制潜伏感染的口腔细胞，促进病毒传播。 临床相关性，我们发现我们的口腔中 Sa、Pg 和 KSHV 的感染率和混合感染率较高 HIV+ 患者队列，发现唾液 ROS、宿主抗氧化因子和细菌水平较高 HIV+/KSHV+ 患者的 LTA/LPS 优于 HIV+/KSHV- 患者。根据这些数据，我们认为。 牙周细菌或其 PAMP 可能促进最初的 KSHV 感染、复制和传播 通过多种宿主和病毒因素在HIV+患者的口腔中发挥作用，最终促进口腔 为了解决这一假设，我们提出了以下具体目标，包括临床目标。 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+ 患者中的因素、特定细菌携带/PAMP 水平和 KSHV 口腔脱落 2) 确定。 牙周细菌或其 PAMP 促进 KSHV 初始感染和病毒裂解的机制 重新激活，KS发展所必需的两个重要步骤，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口腔独特生态位中病毒相关癌症的发展 我们的研究结果也将为临床开发提供框架。 评估干扰宿主-细菌-病毒相互作用的策略的试验（例如特定抗生素、针对 TLRs-ROS 轴或病毒 microRNA 合成）具有减少或预防口腔 KSHV 感染的能力， HIV+ 患者的 KS 进展。

项目成果

The Anti-COVID-19 Drug Remdesivir Promotes Oncogenic Herpesvirus Reactivation through Regulation of Intracellular Signaling Pathways.

抗 COVID-19 药物瑞德西韦通过调节细胞内信号通路促进致癌疱疹病毒重新激活。

• 发表时间: 2022-03-15
• 影响因子: 4.9
• 作者: Chen, Jungang;Dai, Lu;Kendrick, Samantha;Post, Steven R;Qin, Zhiqiang
• 通讯作者: Qin, Zhiqiang

Identification of new antiviral agents against Kaposi's sarcoma-associated herpesvirus (KSHV) by high-throughput drug screening reveals the role of histamine-related signaling in promoting viral lytic reactivation.

通过高通量药物筛选鉴定出针对卡波西肉瘤相关疱疹病毒（KSHV）的新型抗病毒药物，揭示了组胺相关信号在促进病毒裂解再激活中的作用。

• 发表时间: 2019
• 影响因子: 6.7
• 作者: Chen, Jungang;Dai, Lu;Goldstein, Alana;Zhang, Haiwei;Tang, Wei;Forrest, J Craig;Post, Steven R;Chen, Xulin;Qin, Zhiqiang
• 通讯作者: Qin, Zhiqiang

Kaposi Sarcoma-Associated Herpesvirus and Staphylococcus aureus Coinfection in Oral Cavities of HIV-Positive Patients: A Unique Niche for Oncogenic Virus Lytic Reactivation.

HIV 阳性患者口腔中卡波西肉瘤相关疱疹病毒和金黄色葡萄球菌的双重感染：致癌病毒裂解再激活的独特利基。

• 发表时间: 2020
• 作者: Dai, Lu;Qiao, Jing;Yin, Jun;Goldstein, Alana;Lin, Hui;Post, Steven R;Qin, Zhiqiang
• 通讯作者: Qin, Zhiqiang

Expression of PD-1 and PD-Ls in Kaposi's sarcoma and regulation by oncogenic herpesvirus lytic reactivation.

PD-1 和 PD-L 在卡波西肉瘤中的表达以及致癌疱疹病毒裂解再激活的调节。

• DOI: 10.1016/j.virol.2019.07.024
• 发表时间: 2019-10-01
• 期刊: Virology
• 影响因子: 3.7
• 作者: Jungang Chen;L. Del Valle;Hui;Karlie Plaisance;J. Forrest;S. Post;Zhiqiang Qin
• 通讯作者: Zhiqiang Qin

Oral Shedding of an Oncogenic Virus Alters the Oral Microbiome in HIV+ Patients.

致癌病毒的口腔脱落会改变艾滋病毒患者的口腔微生物组。

• 发表时间: 2022
• 作者: Dai, Lu;Lu, Yong;Chen, Jungang;Plaisance;Mu, Shengyu;Forrest, J Craig;Whitby, Denise;Post, Steven R;Qin, Zhiqiang
• 通讯作者: Qin, Zhiqiang