HCMV-mediated repurposing of AMPK & CaMKK signaling for productive infection

人巨细胞病毒（HCMV）是先天性出生缺陷的主要原因，并在婴儿中引起严重疾病。 广泛的免疫抑制患者人群，包括血液癌症患者和移植 受惠人士我们已经发现，HCMV建立了一个前病毒代谢程序，驱动许多细胞凋亡， 支持病毒后代产生的代谢活动。这种代谢重编程的关键方面 包括靶向AMP激活的激酶（AMPK）和钙调蛋白依赖性激酶激酶（CamKK）， 我们发现这两者对于成功的HCMV感染都是至关重要的。此外，我们的数据表明，HCMV UL 26 蛋白质是一种重要的病毒代谢决定因子，其激活脂肪酸生物合成，即代谢途径 对感染至关重要。关于这些因素如何促进代谢重编程，仍存在许多问题 成功感染。为了解决这些问题，我们将追求以下目标：1）阐明如何 AMPK有助于HCMV介导的代谢重编程; 2）确定钙调素依赖性 激酶激酶信号传导有助于HCMV感染;和，3）阐明HCMV UL 26蛋白如何与HCMV感染相关。 有助于病毒的代谢重组我们希望我们的研究结果能够确定 HCMV通过其操纵代谢调节以支持感染的特定机制。的 拟议的工作将扩大我们对一个重要的宿主病原体相互作用的理解，并考虑到这些 过程是必不可少的生产性感染，拟议的实验将突出新的目标， 治疗干预

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. Key aspects of this metabolic reprogramming include targeting the AMP-activated kinase (AMPK) and the calmodulin dependent-kinase kinase (CamKK), both of which we find are critical for successful HCMV infection. Further, our data indicate that the HCMV UL26 protein is an important viral metabolic determinant that activates fatty acid biosynthesis, a metabolic pathway essential for infection. Many questions remain about how these factors contribute to metabolic reprogramming and successful infection. To address these questions, we will pursue the following aims: 1) Elucidate how AMPK contributes to HCMV-mediated metabolic reprogramming; 2) Determine how calmodulin-dependent kinase kinase signaling contributes to HCMV infection; and, 3) Elucidate how the HCMV UL26 protein contributes to viral metabolic reprogramming. We expect the outcome of our research to be the identification of specific mechanisms through which HCMV manipulates metabolic regulation to support infection. 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.