The Viral G-Protein-Coupled Receptor Homologs M33 and US28 Promote Cardiac Dysfunction during Murine Cytomegalovirus Infection.
The Viral G-Protein-Coupled Receptor Homologs M33 and US28 Promote Cardiac Dysfunction during Murine Cytomegalovirus Infection.
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DOI：
10.3390/v15030711
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发表时间：
2023-03-09
期刊：
影响因子：
--
通讯作者：
Cardin RD
中科院分区：
文献类型：
--
作者：
Bonavita CM;White TM;Francis J;Farrell HE;Davis-Poynter NJ;Cardin RD
人巨细胞病毒（HCMV）是一种普遍存在的病原体，感染世界上大多数人口，并导致终身潜伏感染。HCMV已被证明会加重心血管疾病，包括心肌炎、血管硬化和移植血管病。最近，我们已经表明，小鼠巨细胞病毒（MCMV）重演的心血管功能障碍观察患者的HCMV诱导的心肌炎。为了了解CMV诱导的心脏功能障碍中涉及的病毒机制，我们进一步表征了MCMV对心脏功能的反应，并检查了病毒编码的G蛋白偶联受体同源物（vGPCR）US28和M33作为促进心脏感染的潜在因素。我们假设CMV编码的vGPCR可加重心血管损伤和功能障碍。使用三种病毒来评估vGPCR在心功能障碍中的作用：野生型MCMV、M33缺陷型病毒（CMV M33）和M33开放阅读框（ORF）被US 28替换的病毒，HCMV vGPCR（即，US28+）。我们的体内研究表明，M33在急性感染期间通过增加病毒载量和心率来促进心脏功能障碍。在潜伏期，ΔM33感染的小鼠表现出减少钙化，改变细胞基因表达，并减少心脏肥大相比，野生型MCMV感染的小鼠。在ΔM33感染的动物中，来自心脏的离体病毒再激活效率较低。HCMV蛋白US28表达恢复了M33缺陷型病毒从心脏重新激活的能力。US28+ MCMV感染对心脏造成的损害与野生型MCMV感染相当，表明US28蛋白足以补充心脏中M33的功能。总之，这些数据表明vGPCR在心脏病毒发病机制中的作用，因此表明vGPCR促进长期心脏损伤和功能障碍。
Human cytomegalovirus (HCMV) is a ubiquitous pathogen that infects the majority of the world population and causes lifelong latent infection. HCMV has been shown to exacerbate cardiovascular diseases, including myocarditis, vascular sclerosis, and transplant vasculopathy. Recently, we have shown that murine CMV (MCMV) recapitulates the cardiovascular dysfunction observed in patients with HCMV-induced myocarditis. To understand the viral mechanisms involved in CMV-induced heart dysfunction, we further characterized cardiac function in response to MCMV and examined virally encoded G-protein-coupled receptor homologs (vGPCRs) US28 and M33 as potential factors that promote infection in the heart. We hypothesized that the CMV-encoded vGPCRs could exacerbate cardiovascular damage and dysfunction. Three viruses were used to evaluate the role of vGPCRs in cardiac dysfunction: wild-type MCMV, a M33-deficient virus (∆M33), and a virus with the M33 open reading frame (ORF) replaced with US28, an HCMV vGPCR (i.e., US28+). Our in vivo studies revealed that M33 plays a role in promoting cardiac dysfunction by increasing viral load and heart rate during acute infection. During latency, ΔM33-infected mice demonstrated reduced calcification, altered cellular gene expression, and less cardiac hypertrophy compared with wild-type MCMV-infected mice. Ex vivo viral reactivation from hearts was less efficient in ΔM33-infected animals. HCMV protein US28 expression restored the ability of the M33-deficient virus to reactivate from the heart. US28+ MCMV infection caused damage to the heart comparable with wild-type MCMV infection, suggesting that the US28 protein is sufficient to complement the function of M33 in the heart. Altogether, these data suggest a role for vGPCRs in viral pathogenesis in the heart and thus suggest that vGPCRs promote long-term cardiac damage and dysfunction.
影响因子：
3.1
作者：
Bonavita CM;White TM;Stanfield BA;Cardin RD
通讯作者：
Cardin RD
影响因子：
4.7
作者：
Song, Rui;Fullerton, David A.;Ao, Lihua;Zheng, Daniel;Zhao, Ke-seng;Meng, Xianzhong
通讯作者：
Meng, Xianzhong