Background

Numerous studies suggest that cytomegalovirus (CMV) infection may act as isolated risk factor in the development of cardiac allograft vasculopathy (CAV). Viral G protein-coupled receptors (GPCRs) are thought to contribute to the pathogenic changes associated with CMV infection. The aim of this study was to investigate the role of murine cytomegalovirus GPCR M33 in the development of CAV in a murine aortic allograft model.

Methods

MHC I-mismatched aortas of C.B10 (H2^b) mice were transplanted into BALB/c (H2^d) recipients, which were either mock-infected, infected with wild type (WT) MCMV or MCMV with a deleted M33-receptor gene (delM33). Persistence of cytomegalovirus infection was confirmed by qPCR and by luciferase assay to ensure active viral replication. Grafts were harvested on days 21 and 37 for intragraft mRNA expression and histological analysis.

Results

Active viral replication was demonstrated and MCMV presence was confirmed by PCR within spleen, liver, salivary glands, lung and the aortic transplant. Infection with delM33 resulted in significantly less intimal proliferation compared to WT-MCMV but more pronounced proliferation than in mock-infected allografts (32.19% [delM33] vs. 41.71% [WT-MCMV] vs. 24.33% [MCMV-]). Intragraft expression of most analyzed genes was significantly increased in infected mice. VCAM-1, ICAM-1, PDGFβ, CXCR3 and Granzyme B were distinctly less expressed in grafts of delM33 infected compared to WT infected mice. Cellular infiltration revealed reduced dendritic cells and T cells in grafts infected with delM33 compared to WT MCMV.

Conclusions

These data suggest that the MCMV encoded receptor M33 plays an important role as a viral effector mechanism contributing to the development of CAV in a murine aortic transplant model.

中文翻译：

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巨细胞病毒趋化因子受体M33的敲除减少了小鼠主动脉移植模型中的慢性同种异体移植排斥

背景

大量研究表明，巨细胞病毒（CMV）感染可能是心脏同种异体移植血管病（CAV）发生的独立危险因素。病毒G蛋白偶联受体（GPCR）被认为与CMV感染相关的致病性改变。这项研究的目的是调查在小鼠主动脉同种异体移植模型中小鼠巨细胞病毒GPCR M33在CAV发生中的作用。

方法

MHC I不匹配的C.B10（H2 ^b）小鼠主动脉被移植到BALB / c（H2 ^d）受体中，这些受体被模拟感染，被野生型（WT）MCMV感染或被M33受体基因缺失的MCMV感染（delM33）。通过qPCR和荧​​光素酶测定法确认了巨细胞病毒感染的持续性，以确保病毒活跃复制。在第21天和第37天收获移植物，用于移植物内mRNA表达和组织学分析。

结果

证实了病毒的活跃复制，并通过PCR证实了脾，肝，唾液腺，肺和主动脉移植物中MCMV的存在。与WT-MCMV相比，delM33感染导致的内膜增生明显减少，但与模拟感染同种异体移植相比，增生更为明显（32.19％[delM33]对41.71％[WT-MCMV]对24.33％[MCMV-]）。在感染的小鼠中，大多数分析基因的移植物内表达显着增加。与被WT感染的小鼠相比，在被delM33感染的移植物中VCAM-1，ICAM-1，PDGFβ，CXCR3和粒酶B的表达明显减少。与WT MCMV相比，细胞浸润显示感染了delM33的移植物中树突状细胞和T细胞减少。

结论

这些数据表明，MCMV编码的受体M33作为一种病毒效应器机制，在鼠主动脉移植模型中起CAV形成的作用，起着重要作用。