PET imaging of viral infection

许多病毒通过利用宿主细胞提供的核苷酸进行复制来维持寄生生活方式。这个 由SARS-CoV-2引起的冠状病毒病2019年(新冠肺炎)的表现和进展， 一种RNA病毒，伴随着病毒利用宿主的机制在受感染的宿主中扩张。这个 SARS2的快速扩展需要通过RNA合成的挽救途径来增强RNA合成，大多数 尤其是在作为SARS2感染目标的非分裂细胞中。这提供了一个机会 如果有指示病毒RNA合成的成像示踪剂，则跟踪病毒感染的状态。 与宿主相似，病毒相关的RNA合成(病毒基因组RNA或病毒信使RNA)发生在 三个阶段：启动、延长和终止。我们将重点关注病毒相关RNA的延长 合成，即在生长的3‘端重复添加一种核苷一磷酸(NMP) 核糖核糖核酸链。由于SARS2需要大量的宿主细胞尿苷，其基因组的三分之一是尿苷，尿苷是 此外，亚基因组正链RNA合成/病毒功能也需要。相应地，放射性标记 在以下情况下，应使用尿苷通过PET成像跟踪嘧啶代谢，以增强RNA合成 SARS2感染。然而，尿苷代谢进入病毒RNA的特定挽救途径 在感染SARS2的组织中，合成没有上调。然而，5-FU可以直接转化为尿苷 单磷酸(UMP)，用于结合到RNA中。因此，我们建议使用F-18标记的亲药物5- 氟尿嘧啶(5-[18F]FU，与5-FU分子相同，F-19被F-18取代)。 尽管如此，5-[18F]FU的快速分解代谢使PET图像的解释变得模糊，直到添加 防止5-[18F]FU分解代谢以获得有意义的5-[18F]FU的PET图像 [18F]FU摄取。因此，我们建议将5-[18F]FU重新用于SARS2感染的PET成像，并 在建议的PET成像期间，将使用相同的eniluracil来暂时保持5-[18F]FU的完整性。 我们将使用现成的和临床相关的小鼠模型来测试5-[18F]FU的PET成像 肝炎病毒(MHV)感染MHV是一种在结构上与SARS2非常相似的小鼠冠状病毒，可以引起 小鼠和大鼠的多种疾病，包括肝炎、脑脊髓炎、肠炎和呼吸道疾病 疾病。在人类感染SARS2期间，许多相同的器官也受到了类似的影响，尽管 急性肺损伤相关死亡率在公众认知中象征着新冠肺炎。 5-[18F]FU PET显像的临床应用将补充基于聚合酶链式反应的新冠肺炎(GOLD)检测 标准)或基于CT的相关肺部疾病的评估(非特异性评估)。它还可以用来 促进新的抗病毒药物开发(超越雷米昔韦)，以优化治疗剂量和治疗 持续时间，并用于今后的治疗监测。

Many viruses sustain a parasitic lifestyle by exploiting host cell supplies of nucleotides for replication. The manifestation and progression of Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2 (SARS2), an RNA virus, is accompanied by the expansion of the virus in the infected host using host's machinery. The rapid SARS2 expansion requires augmented RNA synthesis via the salvage pathway of RNA synthesis, most especially in the non-dividing cells that are the targets of SARS2 infection. This provides an opportunity to trace the status of viral infection if an imaging tracer that is indicative of viral RNA synthesis is available. Similar to the host, viral related RNA synthesis (viral genomic RNA or viral messenger RNA) occurs in three stages: initiation, elongation and termination. We will focus on the elongation of viral related RNA synthesis, which is the repeated addition of a nucleoside monophosphate (NMP) to the 3’ end of the growing RNA chain. Since SARS2 requires massive amounts of host cell uridine, 1/3 of its genome is uridine, uridine is moreover required for sub-genome positive strand RNA synthesis/viral function. Accordingly, radiolabeled uridine shall be used to track pyrimidine metabolism by PET imaging for augmented RNA synthesis under SARS2 infection. However, the specific salvage pathway of uridine metabolism for incorporation into viral RNA synthesis was not up-regulated in SARS2 infected tissues. Yet, 5-FU can be converted directly into uridine monophosphate (UMP) for incorporated into RNA. We therefore propose to use F-18 labeled pro-drug 5- fluorouracil (5-[18F]FU, the same molecule as 5-FU with isotopic substitution of F-19 by F-18) instead. Still, the rapid catabolism of 5-[18F]FU obscures interpretation of the PET images until the addition of eniluracil (5-ethynyluracil) that prevents the catabolism of 5-[18F]FU to obtain meaningful PET images of 5- [18F]FU uptake. Consequently, we propose to re-purpose 5-[18F]FU for PET imaging of SARS2 infection, and will use the same eniluracil to transiently maintain the integrity of 5-[18F]FU during the proposed PET imaging. We will test PET imaging with 5-[18F]FU using the readily available and clinically relevant model of mouse hepatitis virus (MHV) infection. MHV, a murine coronavirus very similar to SARS2 in structure, can cause a wide range of diseases in the mice and rats, including hepatitis, encephalomyelitis, enteritis, and, respiratory diseases. Many of these same organs were similarly affected during human SARS2 infection even though the acute lung injury related mortality symbolized COVID-19 in the public perception. Clinical utility of 5-[18F]FU PET imaging would be complementing PCR-based testing of COVID-19 (gold standard) or CT-based assessment (non-specific evaluation) of related lung disease. It could also be used to facilitate new anti-viral drug development (beyond remdesivir) for optimizing therapeutic dose and treatment duration, and for treatment monitoring in the future.