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Molecular Features of Congenital Cytomegalovirus Infection in Neonatal Mouse Brain at Single-cell Resolution

ABSTRACT: Cytomegalovirus (CMV) is the leading viral cause of congenital infection, posing a significant risk to fetal brain development with neurodevelopmental sequelae. Effective medical treatments are limited due to an inadequate understanding of the interactions between CMV and the developing brain. Here, we applied single-cell transcriptomics to characterize the molecular features of neonatal mouse brains congenitally infected with murine CMV.

ORGANISM(S): Mus musculus

PROVIDER: GSE282712 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:Background: Congenital cytomegalovirus (cCMV) is a common intrauterine infection, leading to neurodevelopmental disabilities. Early prognostic assessment of the severity of cCMV has remained an ongoing challenge. We aimed to identify amniotic fluid biomarkers of the severity of cCMV-related fetal brain injury. Methods: Global proteome analysis was performed in mid-gestation amniotic fluid samples, comparing fetuses with severe cCMV to asymptomatic CMV-infected fetuses (the discovery cohort). The levels of selected differentially-excreted proteins were further determined by specific immunoassays, and evaluated in an independent validation cohort, including clinically-blinded amniotic fluid of CMV-infected fetuses from unrelated centers. Findings: Proteome analysis identified 29 amniotic fluid proteins with distinct abundance in fetuses with severe-, compared to asymptomatic, cCMV. Pathway analysis of the differentially-excreted proteins revealed enriched pathways of inflammatory response, cellular compromise, immunological disease, organismal injury, and neurological disease, underlining a link between excessive inflammation at the maternal-fetal interface and the development of cCMV-related fetal brain damage. Importantly, the levels of two of these proteins, chemerin and galectin-3-binding protein (Gal-3BP), selected for validation, demonstrated 88.2% sensitivity (each), 100-96.2% specificity, 100-93.8% positive predictive value, and 92.9-92.6% negative predictive value, with 0.98-0.97 area under the curve (for chemerin - Gal-3BP, respectively) in differentiating 17 fetuses with severe cCMV from 26 asymptomatic CMV-infected fetuses. Interpretation: These results identify the immunomodulatory proteins chemerin and Gal-3BP as new highly predictive amniotic fluid biomarkers of cCMV severity, which could guide early prognostic stratification and potential personalized treatment of cCMV-infected fetuses. Funding: Israel Science Foundation; Research Fund of the Hadassah Medical Organization

Project description:Background: Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide, with immune-mediated processes increasingly recognized as important contributors to CVD onset and progression. Seropositivity rates indicate 60–90% of the population carries latent viral infections, e.g., with cytomegalovirus, that profoundly shape the individual immune phenotype. Epidemiological studies have consistently associated cytomegalovirus (CMV) seropositivity with adverse cardiovascular outcomes, yet the functional consequences of latent CVM cytomegalovirus latency in the context of myocardial infarction (MI) have not been studied, nor has its underlying influence on cardiac tissue. Methods: In this study we employed a murine model of cytomegalovirus (MCMV) infection to investigate the impact of the virus in the cardiac immune environment. We characterized the immune cell populations involved in cardiac immune responses by flow cytometry and performed bulk RNA seq of infected and naive mice to dissect the transcriptional differences that occur after viral exposure. To better understand how viral infections affect the myocardium of infected and naive animals post MI, we conducted a series of experiments involving flow cytometry, single-cell RNA / TCR sequencing, echocardiography, and cMRI 5 days after mice underwent experimental MI. Additionally, we used cMRI to stratify CMV- seropositive patients as “good” or “poor healers” and tested their CMV IgG titers. Using TCR-sequencing, we also identified CMV-responding TCRs and compared blood-derived and heart-derived T cells from post-mortem tissues. Results: Our findings show that exposure to murine CMV induces both long-term changes in the cardiac transcriptional profile and alterations in cardiac immune cell populations. We detected the establishment of virus-specific resident memory T cells that persist in cardiac tissue. Following myocardial infarction (MI), mice previously exposed to MCMV had more abundant cardiac-resident T cells, heightened inflammatory profile, and adverse ventricular remodeling, as revealed by MRI, compared to naive controls. These murine observations were supported by data from CMV-seropositive MI patients, who harbored CMV-responsive T cells and exhibited impaired cardiac healing. Conclusions: Taken together, our findings demonstrate that latent CMV infection leads to long-term immunological changes in cardiac tissue that exert significant effects on post-MI healing outcome.

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Molecular Features of Congenital Cytomegalovirus Infection in Neonatal Mouse Brain at Single-cell Resolution

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