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: 10658591
• 负责人: Tiffany Anne Reese
• 金额: $ 48.5万
• 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 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658591
• 关键词: Acids; Address; Animals; Biology; Bone Marrow; Breeding; Cell physiology; Data; Deposition; Diet; Distal; Embryo; Epigenetic Process; Genome; Goals; Grant; Helminths; Herpesviridae; Herpesviridae Infections; Histones; Human; Immune; Immune response; Immune system; Individual; Infection; Interleukin-4; Intestinal parasite; Intestines; Macrophage; Maintenance; Modification; Mus; Nematospiroides dubius; Parasites; Parasitic infection; Peritoneal; Peritoneal Macrophages; Peritoneum; Persons; Phenotype; Population; Reporting; Role; Science; Signal Transduction; System; Time; Tissues; Tretinoin; Viral Genome; Virus; Virus Activation; Virus Diseases; Virus Latency; Vitamin A; Vitamin A Deficiency; Work; chronic infection; co-infection; cytokine; dietary; gammaherpesvirus; helminth infection; immunoregulation; insight; mouse model; pathogen; progenitor; reactivation from latency; response; virtual

PROJECT SUMMARY The goal of this grant is to understand how bystander infections with intestinal parasites alter chronic infection with γ-herpesviruses. This is important because herpesviruses infect virtually all people and approximately a quarter of the world’s population is simultaneously infected with a parasite. Herpesvirus infections are chronic, but these viruses do not persistently replicate in a healthy host. Instead, they establish a quiescent infection, termed latency. We discovered previously that co-infection with an intestinal helminth parasite after infection with γ-herpesvirus led to increased virus reactivation from latency. We detailed a mechanism whereby reactivation of the virus depended on sensing host cytokines produced in response to the parasite. A remaining question is whether the timing of the dual infections is important. In this grant we propose to address this question by changing the order of virus-parasite co- infection to determine whether reactivation of the virus is increased by parasite infection when the parasite infection occurs before the γ-herpesvirus infection. We have data to indicate that prior infection with an intestinal parasite increases γ-herpesvirus reactivation, but that the mechanism is different than what we discovered previously when parasite infection occurs after the herpesvirus infection. We find that parasite infected animals have increased resident peritoneal macrophages. We also find that when retinoic acid, which is required for maintenance of resident peritoneal macrophages, is depleted in mice, parasite infection no longer increases virus reactivation. Our hypothesis is that parasite infection, in a retinoic acid dependent manner, alters the tissue composition of resident macrophages. This promotes retention of a population of infected macrophages with enhanced γ-herpesvirus reactivation. In this proposal, we aim to examine the role of resident macrophages and retinoic acid in parasite-induced herpesvirus reactivation. These studies will deliver insight into the mechanisms that drive herpesvirus reactivation during co-infection and will increase our understanding of parasite modulation of tissue resident macrophages. Harnessing the power of mouse model pathogens, these studies will advance our understanding of pathogen co-infection.

项目总结