Modulation of Innate Immunity by KSHV

KSHV 对先天免疫的调节

• 批准号: 9620767
• 负责人: BLOSSOM A DAMANIA
• 金额: $ 44.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-11 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9620767
• 关键词: Antiviral Response; Binding; Biological; Cell Culture Techniques; Cells; Cyclic GMP; DNA; DNA Viruses; Development; Dinucleoside Phosphates; Disease; Gene Activation; Genes; HIV; HIV Infections; Human; Human Herpesvirus 8; Immune; Immune response; Immune system; Immunosuppression; In Vitro; Incidence; Individual; Infection; Innate Immune Response; Interferons; Kaposi Sarcoma; Life; Liquid substance; Lymphoma; Malignant Neoplasms; Mediating; Natural Immunity; Oral; Oral cavity; Palate Kaposi' s Sarcoma; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Periodicity; Play; Population; Primary Infection; Production; Proteins; Reporting; Role; Route; Saliva; Sexual Transmission; Signal Transduction; Stimulator of Interferon Genes; Sum; Symptoms; Syndrome; Therapeutic immunosuppression; Time; Toll-like receptors; Transplant Recipients; Viral; Viral Genes; Viral Genome; Viral Pathogenesis; Viral Proteins; Virus; Virus Inhibitors; antiretroviral therapy; base; cell type; co-infection; combat; immune reconstitution; in vivo; macrophage; microorganism; monocyte; prevent; reactivation from latency; receptor; recombinant virus; response; sarcoma; sensor; viral interferon regulatory factor-1

PROJECT ABSTRACT KSHV is both a commensal and pathogenic microorganism in the human host. Many studies have shown that KSHV is present in the saliva and oral cavity and can be transmitted through both oral and sexual transmission routes. In conditions of immune suppression e.g. HIV infection or immunosuppressive therapy, KSHV is associated with the development of sarcomas and lymphomas, including in the oral cavity. Although these diseases are usually seen in the context of immune suppression, even HIV- negative individuals can develop KSHV-associated cancers. Thus, it is clear that the host immune system plays a critical role in preventing diseases associated with KSHV infection. It is currently unclear how the immune system keeps KSHV in check in healthy individuals, but allows disease to progress during times of immunosuppression. We have previously reported that TLRs, RLRs and NLRs are capable of detecting KSHV in a variety of different biologically relevant cell types during primary infection and during reactivation from latency. We also reported that the cGAS-STING DNA sensing pathway can detect KSHV during primary infection and reactivation and that KSHV viral proteins can counteract activation of this important pathway. In this application, we propose to determine how KSHV viral proteins modulate cGAS and STING innate immune proteins and allow the virus to successfully establish life-long latency in the human host. We also propose to examine how KSHV's modulation of innate immune pathways impacts HIV infection.

项目摘要 KSHV是人体内的一种共生致病微生物。 许多研究表明，KSHV存在于唾液和口腔中，并可 通过口头和性传播途径传播。在免疫的情况下 抑制，例如艾滋病毒感染或免疫抑制治疗，KSHV与 肉瘤和淋巴瘤的发展，包括在口腔内。虽然 这些疾病通常是在免疫抑制的背景下出现的，甚至是艾滋病毒- 阴性的人会患上与KSHV相关的癌症。因此，很明显， 宿主免疫系统在预防KSHV相关疾病中起着关键作用 感染。 目前尚不清楚免疫系统如何保持KSHV处于健康状态 个体，但允许疾病在免疫抑制时期发展。我们有 此前报道，TLR、RLR和NLR能够检测到KSHV在 不同生物相关细胞类型在初次感染期间和在 从延迟中重新激活。我们还报道了cGAS-STING DNA传感 途径可以检测到KSHV在初次感染和再激活过程中以及KSHV病毒 蛋白质可以抵消这一重要途径的激活。在此应用程序中，我们 建议确定KSHV病毒蛋白如何调节cGAS和先天刺痛 免疫蛋白并允许病毒在体内成功建立终生潜伏期 人类的主人。我们还建议研究KSHV对先天免疫的调节 途径影响艾滋病毒感染。