Niklas M Fritz1, Thomas Stamminger2, Martina Ramsperger-Gleixner1, Annika V Kuckhahn1, Regina Müller3, Michael Weyand1, Christian Heim4. 1. Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Krankenhausstraße 12, 91054 Erlangen, Germany. 2. Institute for Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany. 3. Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany. 4. Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Krankenhausstraße 12, 91054 Erlangen, Germany. Electronic address: christian.heim@fau.de.
Abstract
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 (H2b) mice were transplanted into BALB/c (H2d) 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.
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 (H2b) mice were transplanted into BALB/c (H2d) 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 infectedmice. VCAM-1, ICAM-1, PDGFβ, CXCR3 and Granzyme B were distinctly less expressed in grafts of delM33infected compared to WT infectedmice. 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.
Authors: Jiawei Ma; Kimberley Bruce; Nicholas Davis-Poynter; Philip G Stevenson; Helen E Farrell Journal: J Virol Date: 2021-12-08 Impact factor: 6.549