Dataset Information

Identification of Symptomatic Fetuses Infected with Cytomegalovirus Using Amniotic Fluid Peptide Biomarkers.

ABSTRACT: Cytomegalovirus (CMV) is the most common cause of congenital infection, and is a major cause of sensorineural hearing loss and neurological disabilities. Evaluating the risk for a CMV infected fetus to develop severe clinical symptoms after birth is crucial to provide appropriate guidance to pregnant women who might have to consider termination of pregnancy or experimental prenatal medical therapies. However, establishing the prognosis before birth remains a challenge. This evaluation is currently based upon fetal imaging and fetal biological parameters, but the positive and negative predictive values of these parameters are not optimal, leaving room for the development of new prognostic factors. Here, we compared the amniotic fluid peptidome between asymptomatic fetuses who were born as asymptomatic neonates and symptomatic fetuses who were either terminated in view of severe cerebral lesions or born as severely symptomatic neonates. This comparison allowed us to identify a 34-peptide classifier in a discovery cohort of 13 symptomatic and 13 asymptomatic neonates. This classifier further yielded 89% sensitivity, 75% specificity and an area under the curve of 0.90 to segregate 9 severely symptomatic from 12 asymptomatic neonates in a validation cohort, showing an overall better performance than that of classical fetal laboratory parameters. Pathway analysis of the 34 peptides underlined the role of viral entry in fetuses with severe brain disease as well as the potential importance of both beta-2-microglobulin and adiponectin to protect the injured fetal brain infected with CMV. The results also suggested the mechanistic implication of the T calcium channel alpha-1G (CACNA1G) protein in the development of seizures in severely CMV infected children. These results open a new field for potential therapeutic options. In conclusion, this study demonstrates that amniotic fluid peptidome analysis can effectively predict the severity of congenital CMV infection. This peptidomic classifier may therefore be used in clinical settings during pregnancy to improve prenatal counseling.

SUBMITTER: Desveaux C

PROVIDER: S-EPMC4726449 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of Symptomatic Fetuses Infected with Cytomegalovirus Using Amniotic Fluid Peptide Biomarkers.

Desveaux Cyrille C Klein Julie J Leruez-Ville Marianne M Ramirez-Torres Adela A Lacroix Chrystelle C Breuil Benjamin B Froment Carine C Bascands Jean-Loup JL Schanstra Joost P JP Ville Yves Y

PLoS pathogens 20160125 1

Cytomegalovirus (CMV) is the most common cause of congenital infection, and is a major cause of sensorineural hearing loss and neurological disabilities. Evaluating the risk for a CMV infected fetus to develop severe clinical symptoms after birth is crucial to provide appropriate guidance to pregnant women who might have to consider termination of pregnancy or experimental prenatal medical therapies. However, establishing the prognosis before birth remains a challenge. This evaluation is current ...[more]

PMID: 26808779

Similar Datasets

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:Cell-free RNA in amniotic fluid supernatant reflects developmental changes in gene expression in the living fetus, which includes genes that are specific to the central nervous system. Although it has been previously shown that central nervous system-specific transcripts are present in amniotic fluid supernatant, it is not known whether changes in the amniotic fluid supernatant transcriptome reflect the specific pathophysiologic condition of fetal central nervous system disorders. In myelomeningocele, there is open communication between the central nervous system and amniotic fluid. OBJECTIVES:The purpose of this study was to identify molecular pathophysiologic changes and novel disease mechanisms that are specific to myelomeningocele by the analysis of amniotic fluid supernatant cell-free RNA in fetuses with open myelomeningocele. STUDY DESIGN:Amniotic fluid supernatant was collected from 10 pregnant women at the time of the open myelomeningocele repair in the second trimester (24.5±1.0 weeks); 10 archived amniotic fluid supernatant from sex and gestational age-matched euploid fetuses without myelomeningocele were used as controls (20.9±0.9 weeks). Differentially regulated gene expression patterns were analyzed with the use of human genome expression arrays. RESULTS:Fetuses with myelomeningocele had 284 differentially regulated genes (176 up- and 108 down-regulated) in amniotic fluid supernatant. Known genes that were associated with myelomeningocele (PRICKLE2, GLI3, RAB23, HES1, FOLR1) and novel dysregulated genes were identified in association with neurodevelopment and neuronal regeneration (up-regulated, GAP43 and ZEB1) or axonal growth and guidance (down-regulated, ACAP1). Pathway analysis demonstrated a significant contribution of inflammation to disease and a broad influence of Wnt signaling pathways (Wnt1, Wnt5A, ITPR1). CONCLUSION:Transcriptomic analyses of living fetuses with myelomeningocele with the use of amniotic fluid supernatant cell-free RNA demonstrated differential regulation of specific genes and molecular pathways relevant to this central nervous system disorder, which resulted in a new understanding of pathophysiologic changes. The data also suggested the importance of pathways that involve secondary disease, such as inflammation, in myelomeningocele. These newly identified pathways may lead to hypotheses that can test novel therapeutic targets as adjuncts to fetal surgical repair.

Dataset Information

Identification of Symptomatic Fetuses Infected with Cytomegalovirus Using Amniotic Fluid Peptide Biomarkers.

Publications

Identification of Symptomatic Fetuses Infected with Cytomegalovirus Using Amniotic Fluid Peptide Biomarkers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets