# Fetal and Neonatal Immune Response to Congenital Cytomegalovirus (cCMV) Infection: A Systematically Conducted Scoping Review

## TL;DR

This review summarizes how fetuses and newborns respond to cCMV infection, highlighting immune patterns and their potential impact on long-term health.

## Contribution

The study provides a comprehensive overview of immune responses to cCMV, identifying key immune markers and gaps in understanding.

## Key findings

- cCMV-infected fetuses show strong γδ and CD8+ T-cell responses from the second trimester.
- Neonates exhibit functional NK and CD8+ T-cell responses but impaired CD4+ T-cell responses.
- A 16-gene biosignature is linked to late-onset sensorineural hearing loss in cCMV-infected neonates.

## Abstract

Congenital Cytomegalovirus (cCMV) infection is associated with numerous long-term sequelae. This scoping review consolidates existing evidence on fetal and neonatal immune response to cCMV and their potential relevance to clinical outcomes. A systematic search was conducted in the PubMed database. Observational studies were eligible when full text was available in English and data for immune response (innate, humoral, cellular) and/or immune-related biomarkers (cytokines and molecular markers) were provided. Thirty-four studies were included. CMV-infected fetuses mount robust γδ and CD8+ T-cell responses from the second trimester of pregnancy, with the transcriptomic and cytokine profile of their amniotic fluid revealing upregulation of IFN-γ-inducible genes and cytokines. cCMV-infected neonates mount oligoclonal γδ T-cell responses and functional NK and CD8+ T-cell responses, although data on the latter’s association with symptoms at birth are contradictory. Conversely, CD4+ T-cell responses are impaired, irrespective of symptoms. T cell exhaustion is an emerging finding with unclear implications on long-term outcome. Despite shared transcriptomic profiles between symptomatic and asymptomatic neonates, a 16-gene classifier biosignature has been identified for late-onset sensorineural hearing loss. In conclusion, immune response to cCMV is characterized by a Th1 signature, with T cell exhaustion being an emerging finding warranting further investigation.