Abstract：
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been especially devastating to patients with comorbidities, including metabolic and cardiovascular diseases. Elevated blood glucose during SARS-CoV-2 infection increased mortality of patients with COVID-19, although the mechanisms are not well understood. It has been previously demonstrated that glucose transport and utilization is a crucial pathway for other highly infectious RNA viruses. Thus, we hypothesized that SARS-CoV-2 infection could lead to alterations in cellular and whole body glucose metabolism. Specific pathogen-free domestic cats were intratracheally inoculated with USA-WA1/2020 (wild-type) SARS-CoV-2 or vehicle-inoculated, then euthanized at 4- and 8-days postinoculation (dpi). Blood glucose and cortisol concentrations were elevated at 4 and 8 dpi. Blood ketones, insulin, and angiotensin II concentrations remained unchanged throughout the experimental timeline. SARS-CoV-2 RNA was detected in the lung and heart, without changes in angiotensin-converting enzyme 2 (ACE2) RNA expression. In the lung, SARS-CoV-2 infection increased glucose transporter 1 (GLUT1) protein levels at 4 and 8 dpi, whereas GLUT4 level was only upregulated at 8 dpi. In the heart, GLUT-1 and -4 protein levels remained unchanged. Furthermore, GLUT1 level was upregulated in the skeletal muscle at 8 dpi, and AMPK was activated in the hearts of infected cats. SARS-CoV-2 infection increased blood glucose concentration and pulmonary GLUT protein levels. These findings suggest that SARS-CoV-2 infection induces metabolic reprogramming primarily in the lung to support viral replication. Furthermore, this translational feline model mimicked human COVID-19 and could be used to explore novel therapeutic targets to treat metabolic disease during SARS-CoV-2 infection.NEW & NOTEWORTHY Our study on a feline model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, mirroring human COVID-19, revealed alterations in whole body and cellular glucose metabolism. Infected cats developed mild hyperglycemia, increased protein levels of glucose transporters in the lung, and AMPK activation in the heart. These findings suggest that SARS-CoV-2 infection induces metabolic reprogramming in the cardiorespiratory system to support viral replication. Understanding these mechanisms could lead to novel antiviral therapeutic strategies.
摘要：
严重急性呼吸系统综合症冠状病毒2(SARS-CoV-2)对有合并症的患者尤其具有破坏性，包括代谢和心血管疾病。SARS-CoV-2感染期间血糖升高会增加COVID-19患者的死亡率，虽然机制还没有很好的理解。以前已经证明，葡萄糖的转运和利用是其他高度传染性RNA病毒的关键途径。因此，我们假设SARS-CoV-2感染可导致细胞和全身葡萄糖代谢的改变.用USA-WA1/2020（野生型）SARS-CoV-2或载体接种的无特定病原体家猫进行气管内接种，然后在接种后4天和8天(dpi)处死。血糖和皮质醇浓度在4和8dpi升高。血酮,胰岛素，血管紧张素2浓度在整个实验时间线保持不变。在肺和心脏中检测到SARS-CoV-2RNA，血管紧张素转换酶2（ACE2）RNA表达无变化。在肺部，SARS-CoV-2感染在4和8dpi时增加了葡萄糖转运蛋白1（GLUT1）蛋白水平。,而GLUT4水平仅在8dpi时上调。在心中,GLUT-1和-4蛋白水平保持不变。此外，GLUT1水平在8dpi时在骨骼肌中上调，AMPK在被感染的猫的心脏中被激活。SARS-CoV-2感染增加血糖浓度和肺GLUT蛋白水平。这些发现表明SARS-CoV-2感染主要在肺中诱导代谢重编程以支持病毒复制。此外，这种转化猫模型模拟人类COVID-19，可用于探索治疗SARS-CoV-2感染期间代谢性疾病的新治疗靶点。
