Modulation of DC-SIGN and DC-SIGNR by KSHV

KSHV 调制 DC-SIGN 和 DC-SIGNR

• 批准号: 7494390
• 负责人: ROBERT E MEANS
• 金额: $ 33.3万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494390
• 关键词: Accounting; Adhesions; Antigen Presentation; Antigen-Presenting Cells; Automobile Driving; B-Lymphocytes; Binding; Biology; C Type Lectin Receptors; CD209 gene; CD4 Positive T Lymphocytes; Cancer Etiology; Cell surface; Cells; Cellular biology; Cis-Acting Sequence; Class; Cytolysis; Data; Degradation Pathway; Dendritic Cells; Dominant-Negative Mutation; Down-Regulation; Drug Design; Endocytosis; Endothelial Cells; Family member; Future; Helper-Inducer T-Lymphocyte; Herpesviridae Infections; Homing; Human; Human Herpesvirus 8; Immune; Immune response; Immune system; Immunologic Surveillance; Infection; Intercellular adhesion molecule 1; Invaded; Life; Lymphocyte antigen CD50; MHC Class I Genes; Major Histocompatibility Complex; Membrane Proteins; Molecular; Numbers; Pathogenicity; Pathology; Pathway interactions; Patients; Play; Population; Prevention; Prevention strategy; Production; Prophylactic treatment; Proteins; Public Health; Regulation; Role; Site; Small Interfering RNA; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; Thinking; Toll-like receptors; Ubiquitination; Vaccine Design; Viral; Virus; Virus Diseases; cellular targeting; cytokine; cytotoxic; insight; knock-down; lymph nodes; mutant; pathogen; protein degradation; receptor; research study; response; stable cell line; therapy design; tool; trafficking; transmission process; tumorigenesis; viral detection

DESCRIPTION (provided by applicant): Crucial to any pathogen's replication and spread is an ability to avoid the host's immune responses. An understanding of the molecular mechanisms by which pathogens accomplish this avoidance can be key to the design of treatment and prevention strategies, as well as giving insight into the pathogen response. Kaposi's sarcoma-associated herpesvirus (KSHV), a human pathogen responsible for a large percentage of virally-caused cancers, has evolved a wide variety of strategies for evading or controlling the host immune responses and achieving a life-long, persistent infection. The Mir1 and Mir2 proteins act in concert to remove a number of immunomodulatory proteins from the surface of expressing cells, including MHC class I, B7.2 and ICAM-1. This down regulation results in escape from cytotoxic T lymphocyte and natural killer cell lysis, plus decreased activation of T helper cells. Our lab has discovered two additional targets of regulation, DC-SIGN (CD209) and the related DC-SIGNR. The potential benefits of this down regulation to the biology of the virus are multiple and include an alteration of viral antigen presentation, as well as a potential skewing of the Th1 vs. Th2 immune responses. We also have data demonstrating that both of the SIGN molecules are playing a role in KSHV entry, acting as receptors or accessory molecules. This ability has important implications with regards to the viral transmission, dissemination and pathology. These possibilities will be explored through the following Specific Aims: Specific Aim 1: Molecular mechanisms of KSHV Mir1 and Mir2 modulation of DC-SIGN and DC-SIGNR. Specific Aim 2: The role of DC-SIGN and DC-SIGNR in KSHV infection and pathogenicity. Given the growing numbers of pathogens that utilize DC-SIGN or DC-SIGNR, these experiments will provide important insights into the importance of the SIGN molecules to host immune responses and identify key vulnerabilities that pathogens can exploit. Further, these studies will directly influence the current prophylaxis and treatment strategies used in KSHV-positive patients and in the prevention of KSHV spread. PUBLIC HEALTH RELEVANCE: The Aims of this proposal are to understand the molecular mechanisms by which the Mir1 and Mir2 proteins of Kaposi's sarcoma-associated herpesvirus (KSHV) function in the down regulation of DC-SIGN and DC-SIGNR. Because the SIGN molecules are critical in mounting an effective immune response, this proposal should contribute significantly to understanding the ability of KSHV to avoid the host immune responses, persist and drive oncogenesis.

描述（由申请人提供）：对任何病原体的复制和传播至关重要，是避免宿主免疫反应的能力。对病原体完成这种回避的分子机制的理解可能是设计和预防策略的设计关键，并深入了解病原体反应。卡波西（Kaposi）与肉瘤相关的疱疹病毒（KSHV）是一种负责大部分病毒引起的癌症的人类病原体，已经进化了各种各样的策略，用于逃避或控制寄主免疫反应并实现终身，持续的，持续的感染。 MiR1和MiR2蛋白共同起作用，从表达细胞的表面（包括MHC I类，B7.2和ICAM-1）中去除许多免疫调节蛋白。这种下调导致从细胞毒性T淋巴细胞和天然杀伤细胞裂解中逃脱，加上T辅助细胞的激活降低。我们的实验室发现了其他两个调节目标，即DC-SIGN（CD209）和相关的DC-Signr。这种下调调节对病毒生物学的潜在益处是多重的，包括病毒抗原表现的改变，以及TH1与Th2免疫反应的潜在偏斜。我们还有数据表明，两个符号分子在KSHV进入中都起着作用，充当受体或辅助分子。这种能力在病毒传播，传播和病理方面具有重要意义。这些可能性将通过以下特定目的进行探索：特定目标1：DC-SIGN和DC-SIGNR的KSHV miR1和miR2调制的分子机制。具体目标2：DC-SIGN和DC-SIGNR在KSHV感染和致病性中的作用。鉴于利用DC-SIGN或DC-SIGNR的病原体数量越来越多，这些实验将为符号分子对托管免疫反应的重要性提供重要的见解，并确定病原体可以利用的关键脆弱性。此外，这些研究将直接影响KSHV阳性患者和预防KSHV扩散的当前预防和治疗策略。公共卫生相关性：该提案的目的是了解Kaposi肉瘤相关疱疹病毒（KSHV）功能在DC-SIGN和DC-SIGNR的下调中的MiR1和MiR2蛋白的分子机制。由于符号分子对于安装有效的免疫反应至关重要，因此该建议应显着贡献KSHV避免宿主免疫反应，持久和驱动造成肿瘤的能力。