Defining Mechanisms for Parasite-Driven Effects on Gamma-Herpesvirus Latency

定义寄生虫驱动的对 γ-疱疹病毒潜伏期影响的机制

• 批准号: 9755348
• 负责人: Tiffany Anne Reese
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755348
• 关键词: Acute; B-Lymphocytes; Cells; Chronic; Cytokine Signaling; Disease; Elements; Exposure to; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Genes; Goals; Grant; Helminths; Herpesviridae; Herpesviridae Infections; Human; Immune response; Immune system; In Vitro; Infection; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Intestines; Knowledge; Latent Virus; Life; Lymphoma; Lytic; Mediating; Molecular; Mus; Parasites; Parasitic infection; Pathology; Phenotype; Play; Population; Receptor Signaling; Regulation; Reporting; Role; STAT6 Transcription Factor; Signal Transduction; Switch Genes; System; Testing; Viral; Viral Genes; Viral Genome; Virus; Virus Latency; Work; acute infection; cell type; chronic infection; co-infection; cytokine; defined contribution; experimental study; gammaherpesvirus; genetic manipulation; gut microbiota; helminth infection; in vivo; insight; latent infection; lytic replication; macrophage; microbial community; novel; promoter; reactivation from latency; receptor binding; tumor; virome; virtual

PROJECT SUMMARY The goal of this grant is to understand how bystander infections alter chronic infection with γ- herpesviruses. This is important because herpesviruses infect virtually all people and persist for the life of the host. This means that herpesvirus infection is potentially altered by exposure to bystander infections. Even though herpesvirus infections are chronic, these viruses do not persistently replicate in a healthy host. Instead, they establish a quiescent infection, termed latency. This latent infection with herpesviruses is tightly controlled by the host immune system, and changes in the immune system modulate the state of herpesvirus infection, leading to virus reactivation from latency. We found that co-infection with an intestinal helminth parasite induced γ-herpesvirus reactivation. We identified the host cytokines, interleukin (IL)-4 and IL-13 that are produced during helminth infection to be critical for γ-herpesvirus reactivation. We also identified a viral promoter that is directly regulated by IL-4/IL-13 signaling. However, the mechanisms for helminth-mediated herpesvirus reactivation in vivo are still incompletely understood. We will leverage our unique experimental systems of herpesvirus-helminth co-infection to explore these mechanisms in the mouse. We hypothesize that parasite infection has multiple effects of γ-herpesvirus infection that are dependent on the timing or order of the dual infections. We propose to further detail the requirements for IL-4/IL-13 signaling in herpesvirus- helminth co-infection, and to define the contribution of infection timing to the phenotypes observed. This proposal will increase our understanding of host regulation of herpesvirus latency and the role bystander infections play in herpesvirus infection. This is critical to understanding how these viruses drive pathologies and alter the host immune system.

项目摘要 这项资助的目标是了解旁观者感染如何改变γ- 疱疹病毒这一点很重要，因为疱疹病毒感染几乎所有人，并持续一生 主机的。这意味着疱疹病毒感染可能通过暴露于旁观者而改变 感染.尽管疱疹病毒感染是慢性的，但这些病毒不会持续复制。 健康的宿主相反，他们建立一个静止的感染，称为潜伏期。这种潜在的感染 疱疹病毒受宿主免疫系统的严格控制，免疫系统的变化 调节疱疹病毒感染的状态，导致病毒从潜伏期重新激活。我们发现 与肠道蠕虫寄生虫共感染诱导γ-疱疹病毒再活化。我们确定了 在蠕虫感染期间产生的宿主细胞因子，白细胞介素（IL）-4和IL-13对于 γ-疱疹病毒再激活。我们还鉴定了一个受IL-4/IL-13直接调控的病毒启动子 信号然而，蠕虫介导的疱疹病毒体内再激活的机制仍然是未知的。 不完全理解。我们将利用我们独特的疱疹病毒蠕虫实验系统 共同感染，以探索这些机制的小鼠。我们假设寄生虫感染 γ-疱疹病毒感染的多重效应取决于双重感染的时间或顺序 感染.我们建议进一步详细说明疱疹病毒中IL-4/IL-13信号传导的要求- 蠕虫共感染，并确定感染时间对观察到的表型的贡献。 这一建议将增加我们对宿主调节疱疹病毒潜伏期的认识和作用 旁观者感染在疱疹病毒感染中起作用。这对于理解这些病毒 驱动病理改变宿主免疫系统