CMV UL144 targets the HVEM-BTLA cosignaling system

CMV UL144 针对 HVEM-BTLA 联合信号系统

• 批准号: 7916236
• 负责人: CHRISTOPHER A BENEDICT
• 金额: $ 42.5万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-28 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916236
• 关键词: Address; Affinity; Antibodies; Antigens; Antiviral Agents; Binding; Biological Models; CD4 Positive T Lymphocytes; Cells; Cellular Tropism; Clinical; Cysteine-Rich Domain; Cytomegalovirus; Data; Dendritic Cells; Disease; Down-Regulation; Epithelial Cells; Event; Family; Fibroblasts; Hand; Herpesviridae; Human; Immune; Immune response; Immune system; Immunity; Individual; Infection; Ligand Binding; Ligands; Light; Mediating; Molecular; N-terminal; NK Cell Activation; Orphan; Pattern; Play; Production; Proteins; Reagent; Regulation; Relative (related person); Role; Signal Transduction; Stromal Cells; Structure-Activity Relationship; Surface; System; T-Cell Proliferation; T-Lymphocyte; TNF gene; Testing; Translating; Tropism; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Variant; Viral; Virulent; Virus; Work; cell type; cytokine; herpesvirus entry mediator; inhibitor/antagonist; member; mutant; receptor; stable cell line; tumor necrosis factor receptor binding

Summary This project is directed towards uncovering the role that UL144, an orthologue of the herpesvirus entry mediator (HVEM, a TNFR superfamily member) encoded by virulent strains of human cytomegalovirus (HCMV, a b-herpesvirus), plays in modulating the host immune response. HCMV causes serious clinical complications in immunoncompromised individuals, and disease is associated with the loss of anti-HCMV T cell immunity. HVEM binds to many ligands, including the B and T lymphocyte attenuator (BTLA), a negative cosignaling receptor of the Ig-family that inhibits T-cell proliferation. Importantly, the HVEM-BTLA interaction serves as the first known example of a TNFR binding to a non TNF-related ligand. Until recently UL144 was an orphan receptor, but we have shown UL144 binds BTLA and can inhibit activation of BTLA-expressing T-cells. UL144 primary sequence is highly variable between clinical isolates of HCMV, segregating into three related groups, but all UL144 variants retain the ability to bind BTLA. This proposal aims to characterize the structure/function relationship of the UL144-BTLA interaction using both generated mutants and natural variants of UL144. Additionally, the relative ability of UL144 variants to modulate the activation/function of BTLA-expressing cells will be examined. Finally, the potential of UL144 to modulate BTLA-dependent events will be examined in various HCMV infected cell types using both wild-type and UL144-deficient viruses. This work will shed light upon whether UL144 targeting of the HVEM-BTLA cosignaling network contributes to HCMV modulation of the host anti-viral immune response, perhaps facilitating the establishment of lifelong infection.

概括 该项目致力于揭示疱疹病毒条目的直系同源的UL144的角色 介体（HVEM，TNFR超家族成员）由人类巨细胞病毒的毒素菌株编码（HCMV， b herpesvirus），在调节宿主免疫反应时发挥作用。 HCMV导致严重的临床并发症 在免疫促进的个体中，疾病与抗HCMV T细胞免疫的丧失有关。 HVEM与许多配体结合，包括B和T淋巴细胞衰减剂（BTLA），这是负共鉴定的 抑制T细胞增殖的Ig家族的受体。重要的是，HVEM-BTLA相互作用是 TNFR结合与非TNF相关配体的第一个已知示例。直到最近UL144还是孤儿 受体，但我们显示的UL144结合了BTLA，可以抑制表达BTLA的T细胞的激活。 UL144 一级序列在HCMV的临床分离株之间高度变化，分为三个相关组， 但是所有UL144变体都保留了结合BTLA的能力。该建议旨在表征结构/功能 使用产生的突变体和UL144的自然变体的UL144-BTLA相互作用的关系。 另外，UL144变体的相对能力调节表达BTLA的细胞的激活/功能 将被检查。最后，将检查UL144调节BTLA依赖性事件的潜力 使用野生型和UL144缺陷病毒的各种HCMV感染细胞类型。这项工作将浮出水面 在UL144是否靶向HVEM-BTLA共同信号网络有助于HCMV调制 宿主抗病毒免疫反应，也许促进了终身感染的建立。