Cytomegalovirus chemokine receptor M33 knockout reduces chronic allograft rejection in a murine aortic transplant model

Fritz, Norbert; Stamminger, Thomas; Ramsperger-Gleixner, M.; Kuckhahn, Annika; Müller, Regina; Weyand, Michael; Heim, Christian

doi:10.1016/j.trim.2020.101359

Cited by 7 publications

(5 citation statements)

References 50 publications

(7 reference statements)

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“…This suggests a role for M33 in the modulation of cytokine production in the heart. Recently, similar results have been found in aortic allografts at 30 dpi, where IL10 expression was significantly upregulated in the absence of M33 when compared with the wild-type MCMV-infected grafts [ 26 ]. Together, Figure 4 and Figure 5 demonstrate that MCMV infection causes long-term phenotypic changes in the heart and that M33 may play a role in this modulation, as demonstrated by the reduced calcification and altered gene expression observed in the absence of the M33 protein.…”

Section: Resultssupporting

confidence: 74%

“…Both US28 and M33 are known to modulate many signaling pathways responsible for cellular remodeling, angiogenesis, proliferation, and migration [ 28 , 34 , 43 , 58 , 59 , 60 , 61 ]. Furthermore, US28 has been implicated in the viral modulation that exacerbates the development of chronic diseases [ 1 , 25 , 26 ]. Additionally, M33 plays a role in MCMV latency and reactivation [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our current studies show virally encoded G-protein-coupled receptor homologs (vGPCRs) as a possible mechanism at play during the infection of the heart. Further, vGPCRs play a role in viral pathogenesis by modulating host signaling, immune evasion, and latency [ 21 , 22 , 23 , 24 ], and vGPCRs have also been implicated in contributing to HCMV-associated chronic diseases, including some cancers and cardiovascular diseases [ 1 , 25 , 26 ]. Thus, we focused our investigations on M33, an MCMV vGPCR, and its functional homolog in HCMV, US28 [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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The Viral G-Protein-Coupled Receptor Homologs M33 and US28 Promote Cardiac Dysfunction during Murine Cytomegalovirus Infection

Bonavita

White

Francis

et al. 2023

Viruses

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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.

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Section: Resultssupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Viral G-Protein-Coupled Receptor Homologs M33 and US28 Promote Cardiac Dysfunction during Murine Cytomegalovirus Infection

Bonavita

White

Francis

et al. 2023

Viruses

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“…Our initial hypothesis that the high-risk CMV combination (D + R -) would be a significant risk factor for developing CAV, and thereby reduce posttransplant survival, was not fully supported by this ISHLT Registry analysis, in that we did see an increase in mortality, but not in the incidence of CAV. Although experimental transplant models support the association between CMV and CAV, 10,[15][16][17][18] the exact mechanisms of CMV on the human immune system are still an objective of research. An immunomodulatory effect of CMV 7,19 may be an explanation of contradicting results, as CMV infection possibly leads to various responses of the immune system in different individuals and species.…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus Donor Seropositivity Negatively Affects Survival After Heart Transplantation

et al. 2022

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Background. Prior studies have shown that cytomegalovirus (CMV) infection is a risk factor for the development of cardiac allograft vasculopathy (CAV) and is associated with reduced long-term survival after heart transplantation (HTx). The aim of this International Society for Heart and Lung Transplantation Transplant Registry study was to compare posttransplant survival in different CMV donor:recipient serologic combinations. Methods. We performed a retrospective cohort study, using the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, on 15 885 adult primary heart transplant recipients with known CMV serologic status between July 2004 and June 2014. Posttransplant survival and risk of developing CAV were compared across 4 groups: CMV-seronegative recipients (R–) receiving CMV-positive grafts (D+), intermediate-risk patients (D+R+ and D–R+), and low-risk patients (D–R–). Results. Baseline characteristics (donor/recipient age, body mass index, recipient serum creatinine, blood group, donor cause of death, recipient diagnosis, and ischemic time) were mostly balanced between the groups. Kaplan-Meier survival analyses over a follow-up of 10 y revealed significantly worse survival for both D+ groups as compared to the CMV low-risk group (D+R+: 56.61% [95% confidence interval, 53.94-59.41] versus D–R–: 63.09% [59.74-66.64] P < 0.01 and D+R–: 57.69% [56.03-59.39] versus D–R–; P < 0.001), whereas recipient seropositivity alone was not associated with reduced survival (D–R+ versus D–R– P = 0.178). The risk of developing CAV after HTx was not significantly increased in D+ as compared to D– groups. Conclusions. In a large contemporary cohort, CMV status at the time of HTx was not associated with CAV development. However, there was a significant association between donor CMV seropositivity and reduced short- and long-term survival after HTx. Approaches to mitigate the impact of CMV on posttransplant survival are needed.

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“…Both the HCMV-encoded vGPCR, US28, and the MCMV-encoded functional homolog, M33, activate multiple signaling pathways, which could modulate downstream cellular functions and contribute to the changes that occur in the heart [ 81 ]. A recent publication demonstrated in aortic allograft transplants that the absence of M33 during MCMV infection results in altered cell proliferation, adhesion molecule expression, and immune cell infiltration, thus suggesting that the vGPCRs could influence cardiac damage and dysfunction [ 82 ]. Current studies in our lab are underway to determine various viral and host factors which contribute to cardiac dysfunction following MCMV infection.…”

Section: Discussionmentioning

confidence: 99%

Don’t Go Breaking My Heart: MCMV as a Model for HCMV-Associated Cardiovascular Diseases

Bonavita

Cardin

2021

Pathogens

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Human Cytomegalovirus (HCMV) is a widespread pathogen that causes lifelong latent infection and is associated with the exacerbation of chronic inflammatory diseases in seropositive individuals. Of particular impact, HCMV infection is known to worsen many cardiovascular diseases including myocarditis, atherosclerosis, hypertension, and transplant vasculopathy. Due to its similarity to HCMV, murine CMV (MCMV) is an appropriate model to understand HCMV-induced pathogenesis in the heart and vasculature. MCMV shares similar sequence homology and recapitulates much of the HCMV pathogenesis, including HCMV-induced cardiovascular diseases. This review provides insight into HCMV-associated cardiovascular diseases and the murine model of MCMV infection, which has been used to study the viral pathogenesis and mechanisms contributing to cardiovascular diseases. Our new functional studies using echocardiography demonstrate tachycardia and hypertrophy in the mouse, similar to HCMV-induced myocarditis in humans. For the first time, we show long term heart dysfunction and that MCMV reactivates from latency in the heart, which raises the intriguing idea that HCMV latency and frequent virus reactivation perturbs long term cardiovascular function.

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Cytomegalovirus chemokine receptor M33 knockout reduces chronic allograft rejection in a murine aortic transplant model

Cited by 7 publications

References 50 publications

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

Cytomegalovirus Donor Seropositivity Negatively Affects Survival After Heart Transplantation

Don’t Go Breaking My Heart: MCMV as a Model for HCMV-Associated Cardiovascular Diseases

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