Metabolite-mediated Signaling in Cell-to-Cell Spread of Human Cytomegalovirus

人巨细胞病毒细胞间传播中代谢介导的信号转导

• 批准号: 10403581
• 负责人: John Gerard Purdy
• 金额: $ 37万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-10 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403581
• 关键词: Address; Antiviral Agents; Antiviral Response; Area; Aryl Hydrocarbon Receptor; Attention; Attenuated; Binding; Biological Assay; Biological Process; Biology; CRISPR/Cas technology; Cause of Death; Cells; Clinical; Cytomegalovirus; Cytomegalovirus Infections; Data; Disease; Engineering; Enzymes; Equilibrium; Goals; Health; Human; Hypoxia Inducible Factor; Immune response; Immune system; Infection; Knowledge; Kynurenine; Lead; Life; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Organ; Pathogenesis; Pathway interactions; Pregnancy; Process; Production; Proteins; Proviruses; Research; Role; Signal Pathway; Signal Transduction; Solid; Stem cell transplant; Transplant Recipients; Tryptophan Metabolism Pathway; Vaccines; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; attenuation; base; chronic infection; congenital infection; disability; extracellular; human pathogen; metabolomics; novel; novel strategies; novel therapeutic intervention; prevent; receptor internalization; response; virus host interaction

Human cytomegalovirus (HCMV) establishes a life-long persistent infection by evading the immune system, in part, by direct cell-to-cell viral spread. In solid organ or stem cell transplant recipients, HCMV spread leads to end-organ diseases that can cause death. During pregnancy, HCMV spread causes congenital infection and is a leading cause of congenital disabilities. No HCMV treatment offers a cure, and there is no vaccine. Thus, there is a need for new treatments to limit infection based on novel discoveries in HCMV biology. Viral proteins required for HCMV cell-to-cell spread are known, but the host processes involved in HCMV cell-to-cell spread have received less attention. Clinical strains of HCMV spread most efficiently through cell-to-cell means, but the molecular mechanisms—including host metabolic ones—essential to HCMV cell-to-cell spread are largely unknown. Understanding host mechanisms regulating cell-to-cell spread may lead to new understandings of how to reduce HCMV infection. Our research has uncovered a novel role of metabolite signaling in promoting HCMV spread. This project's overall goal is to mechanistically understand virus-host interactions regulating metabolite signaling essential to HCMV cell-to-cell spread. We found a metabolite in tryptophan metabolism—kynurenine (KYN)—enhances HCMV spread. In addition to its metabolic role, KYN is a signaling messenger. KYN signals through aryl hydrocarbon receptor (AhR). We show that activation of AhR supports HCMV replication. Moreover, we found that hypoxia-inducible factor 1α (HIF1α), through its metabolic regulatory function, limits the production of KYN and suppresses HCMV infection. We hypothesize that metabolite-mediated signaling from infected cells to uninfected cells promotes HCMV cell-to-cell spread, which is attenuated by a HIF1α-dependent cellular response. The proposed research will determine molecular mechanisms involved in the enhancement of HCMV infection by KYN-metabolite signaling (aim 1) and define virus-host interactions regulating HIF1α attenuation of HCMV cell-to-cell spread (aim 2). The experimental approach will integrate virus assays, CRISPR/Cas9 engineering, and untargeted metabolomics to understand HCMV biology. Our findings will provide a mechanistic understanding of metabolite signaling and AhR activity in promoting HCMV cell-to-cell spread and the HIF1α-dependent host-response that targets metabolite signaling to reduce infection. Our studies will advance our knowledge in an understudied area of HCMV research that will provide significant steps-forward in developing novel strategies to treat HCMV infection and limit HCMV-related disease.

人类巨细胞病毒（HCMV）通过直接通过直接的细胞到细胞病毒扩散来避免免疫系统来建立终生的持续感染。在固体器官或干细胞移植受者中，HCMV扩散导致可能导致死亡的末期疾病。在怀孕期间，HCMV传播会引起先天性感染，并且是先天性疾病的主要原因。没有HCMV治疗可以治愈，也没有疫苗。这是需要新的治疗方法来限制基于HCMV生物学中新发现的感染。已知HCMV细胞到细胞扩散所需的病毒蛋白，但是HCMV细胞到细胞扩散所涉及的宿主过程受到较少的关注。 HCMV的临床菌株通过细胞到细胞的平均含量最有效，但是分子机制（包括宿主代谢的机制）与HCMV细胞到细胞的扩散至少是未知的。了解调节细胞间扩散的宿主机制可能会导致对如何减少HCMV感染的新理解。我们的研究发现了代谢物信号传导在促进HCMV扩散中的新作用。该项目的总体目标是机械地了解调节HCMV细胞到细胞扩散所必需的代谢物信号的病毒宿主相互作用。我们在色氨酸代谢（Kynrine（Kyn））中发现了一种代谢产物 - 增强性HCMV传播。除了代谢作用外，Kyn还是信号使者。 Kyn通过芳基烃受体（AHR）信号。我们表明，AHR的激活支持HCMV复制。此外，我们发现低氧诱导因子1α（HIF1α）通过其代谢调节功能限制了KYN的产生并抑制HCMV感染。我们假设从感染细胞到未感染细胞的代谢产物介导的信号传导促进了HCMV细胞对细胞扩散，这会因HIF1α依赖性细胞反应而减弱。拟议的研究将确定Kyn-Inetabolite信号传导增强HCMV感染的分子机制（AIM 1），并定义了治疗HCMV细胞对细胞扩散的HIF1α衰减的病毒 - 宿主相互作用（AIM 2）。实验方法将整合病毒测定，CRISPR/CAS9工程和未靶向的代谢组学以了解HCMV生物学。我们的发现将在促进HCMV细胞间扩散和HIF1α依赖性宿主反应中对代谢产物信号传导和AHR活性提供机械理解，该宿主反应靶向代谢物信号以减少感染。我们的研究将在HCMV研究的知识领域中提高我们的知识，该研究将在制定治疗HCMV感染并限制与HCMV相关疾病的新型策略方面提供重要的步骤。