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

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。代谢重新编程的关键方面 包括靶向AMP激活的激酶(AMPK)和钙调蛋白依赖的激酶(CamKK)， 我们发现，这两个因素对成功感染人巨细胞病毒至关重要。此外，我们的数据表明，HCMV UL26 蛋白质是一种重要的病毒代谢决定因素，可激活代谢途径--脂肪酸的生物合成 对感染是必不可少的。关于这些因素如何对代谢重新编程起作用，仍有许多问题 以及成功的感染。为了解决这些问题，我们将追求以下目标：1)阐明如何 AMPK参与巨细胞病毒介导的代谢重编程；2)确定钙调蛋白依赖的方式 激酶信号转导与巨细胞病毒感染有关；以及，3)阐明巨细胞病毒UL26蛋白如何 有助于病毒代谢的重新编程。我们预计我们的研究结果将确定 巨细胞病毒通过操纵代谢调节来支持感染的特定机制。这个 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. 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.