Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Krankenhausstraße 12, 91054 Erlangen, Germany.
Institute for Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
Transpl Immunol. 2021 Feb;64:101359. doi: 10.1016/j.trim.2020.101359. Epub 2020 Dec 7.
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.
MHC I-mismatched aortas of C.B10 (H2) mice were transplanted into BALB/c (H2) 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.
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.
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.
大量研究表明巨细胞病毒（CMV）感染可能是心脏移植血管病（CAV）发展的孤立危险因素。病毒 G 蛋白偶联受体（GPCR）被认为有助于与 CMV 感染相关的致病变化。本研究旨在探讨鼠巨细胞病毒 GPCR M33 在鼠主动脉同种异体移植模型中 CAV 发展中的作用。
将 MHC I 错配的 C.B10（H2）主动脉移植到 BALB/c（H2）受体中，这些受体要么被模拟感染，要么感染野生型（WT）MCMV 或缺失 M33 受体基因（delM33）的 MCMV。通过 qPCR 和荧光素酶测定来证实持续的巨细胞病毒感染，以确保病毒的复制。在第 21 天和 37 天收获移植物，进行移植物内 mRNA 表达和组织学分析。
通过 PCR 证实了脾、肝、唾液腺、肺和主动脉移植中存在活跃的病毒复制和 MCMV 存在。与 WT-MCMV 相比，delM33 感染导致内膜增殖明显减少，但与 mock 感染的同种异体移植物相比增殖更明显（32.19%[delM33] vs. 41.71%[WT-MCMV] vs. 24.33%[MCMV-]）。感染小鼠中大多数分析基因的表达明显增加。与 WT 感染小鼠相比，delM33 感染的移植物中 VCAM-1、ICAM-1、PDGFβ、CXCR3 和颗粒酶 B 的表达明显减少。与 WT-MCMV 感染的移植物相比，delM33 感染的移植物中树突状细胞和 T 细胞的浸润减少。
这些数据表明，MCMV 编码的受体 M33 作为一种病毒效应机制，在鼠主动脉移植模型中 CAV 的发展中起着重要作用。
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