Metabolic modulation by the HCMV UL38 gene

人类巨细胞病毒(HCMV)是导致先天性出生缺陷和严重疾病的主要原因。 各种各样的免疫抑制患者群体，包括血液病患者和移植患者 收件人。我们已经发现，HCMV启动了一种亲病毒的代谢程序，驱动了许多细胞 支持病毒后代产生的代谢活动。最近，我们发现HCMV UL38 蛋白质是驱动巨细胞病毒诱导的代谢重塑的许多方面所必需和充分的，而我们 假设UL38通过抑制TSC2肿瘤抑制蛋白诱导感染来支持感染 代谢调节。我们将在目标1中通过阐明UL38-TSC2介导的代谢来检验这一假设 重塑是人巨细胞病毒感染的重要原因。此外，我们还发现，巨细胞病毒可诱导神经细胞的表达。 烯醇化酶2(enolase 2，ENO2)，我们发现它对人巨细胞病毒(HCMV)的强大感染很重要。我们假设ENO2的诱导 是巨细胞病毒介导的代谢调节的关键，我们将在目标2中进行测试。最后，我们发现两种巨细胞病毒 感染和UL38的表达使细胞对代谢扰动敏感，揭示了可能 有可能成为治疗的靶点。我们假设HCMV感染和UL38的表达诱导了一种 代谢僵硬的状态，使细胞对代谢挑战敏感，我们将在目标3中验证这一假设。 拟议的工作将扩大我们对一种重要的宿主病原体相互作用的理解，并鉴于这些 过程对于生产性感染是必不可少的，拟议的实验将突出新的目标 治疗性干预。

Human Cytomegalovirus (HCMV) is a major cause of congenital birth defects and causes severe disease in a wide variety of immunosuppressed patient populations, including hematological cancer patients and transplant recipients. We have found that HCMV institutes a pro-viral metabolic program that drives numerous cellular metabolic activities to support the production of viral progeny. More recently, we find that the HCMV UL38 protein is necessary and sufficient to drive many aspects of HCMV-induced metabolic remodeling, and we hypothesize that UL38 supports infection through its inhibition of the TSC2 tumor suppressor protein to induce metabolic modulation. We will test this hypothesis in Aim 1 by elucidating how UL38-TSC2-mediated metabolic remodeling contributes to HCMV infection. In addition, we find that HCMV-induces the expression of neuronal enolase 2 (ENO2), which we find is important for robust HCMV infection. We hypothesize that ENO2 induction is critical for HCMV-mediated metabolic modulation, which we will test in Aim 2. Lastly, we find that both HCMV infection and UL38 expression sensitizes cells to metabolic perturbations, revealing vulnerabilities that could potentially be targeted therapeutically. We hypothesize that HCMV infection and UL38 expression induces a metabolically rigid state that sensitizes cells to metabolic challenges, a hypothesis we will test in Aim 3. The proposed work will broaden our understanding of an important host pathogen interaction, and given that these processes are essential for productive infection, the proposed experiments will highlight novel targets for therapeutic intervention.