Disruption of Type I Interferon Induction by a KSHV Homologue of IPS-1

IPS-1 的 KSHV 同系物对 I 型干扰素诱导的破坏

基本信息

批准号：
10258718
负责人：
DAVID JESSE SANCHEZ
金额：
$ 34.72万
依托单位：
WESTERN UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10258718
关键词：
Acquired Immunodeficiency Syndrome Adaptor Signaling Protein Antiviral Agents Antiviral Response Biochemical Cancerous Clinical Cloning Dangerousness Data Development Disease Dominant-Negative Mutation Endothelial Cells Genes Genome Goals Herpesviridae Infections Homologous Gene Human Human Herpesvirus 8 Immune Immune signaling Immunocompromised Host Immunologic Receptors Impairment Individual Infection Innate Immune Response Innate Immune System Interferon Type I Interferons Kaposi Sarcoma Laboratories Lead Malignant Neoplasms Maps Names Natural Immunity Nucleic Acids Open Reading Frames Pathogenesis Pathologic Pathology Pathway interactions Patients Production Proteins Research Role Severities Signal Induction Signal Transduction Signaling Protein System TNF receptor-associated factor 3 Viral Viral Proteins Virus Virus Diseases Virus Replication Work cytokine immune activation immunoregulation lytic replication novel pathogen tumor

项目摘要

Project Abstract Herpes infections represent one of the most common viral infections that exists in the world. These viruses can be subclinical or as in the case of Kaposi’s Sarcoma Associated Herpesvirus (KSHV) they can lead to dangerous diseases such as cancer. KSHV is well known in AIDS patients to cause Kaposi’s Sarcoma (KS) and several other lymphoproliferartive diseases. Type I Interferon is well known to be the body’s natural anti- viral system and almost all viruses that cause infection in humans have devolved ways to block or use this system to enhance their replication in the host. We have found a novel ORF within the genome of KSHV that seems to be a viral homologue of the IPS1 protein, a critical adaptor of the Type I Interferon induction pathway. This protein is highly expressed during KSHV lytic viral replication. The overall goal of this application is to determine how KSHV uses this novel viral protein to manipulate the innate immune system that should normally limit KSHV replication. In the first specific aim, we will focus on determining how KSHV uses this gene to disrupt IFN as well as replicate efficiently. In the second aim, we plan to determine the importance of this novel gene by the construction and characterization of a KSHV deficient in this viral homologue of IPS1. The long-term goal of this project is to determine how KSHV immune modulation occurs in the goal of blocking this manipulation and limiting KSHV replication.

项目摘要疱疹感染是世界上最常见的病毒感染之一。可能是亚临床的，或者如卡波西肉瘤相关疱疹病毒 (KSHV) 的情况，它们可能导致众所周知，癌症等危险疾病会导致艾滋病患者出现卡波西肉瘤 (KS)。众所周知，I 型干扰素是人体的天然抗病毒药物。病毒系统和几乎所有引起人类感染的病毒都已发展出阻止或使用这种病毒的方法我们在 KSHV 基因组中发现了一个新的 ORF，它可以增强它们在宿主中的复制。似乎是 IPS1 蛋白的病毒同源物，IPS1 蛋白是 I 型干扰素诱导途径的关键适配器。该蛋白在 KSHV 裂解病毒复制过程中高度表达。该应用的总体目标是确定 KSHV 如何使用这种新型病毒蛋白来操纵先天免疫系统通常限制 KSHV 复制在第一个具体目标中，我们将重点确定 KSHV 如何使用它。在第二个目标中，我们计划确定干扰素基因的重要性。通过构建和表征缺乏 IPS1 病毒同源物的 KSHV，我们发现了这种新基因。该项目的长期目标是确定 KSHV 免疫调节如何发生以达到阻断的目的这种操纵并限制 KSHV 复制。