# Cytomegalovirus-encoded immediate early 1 protein perturbs neural progenitor proliferation via interfering with host PML–DISC1 interaction

## TL;DR

This study shows how a virus protein disrupts brain cell growth in congenital CMV infection, leading to developmental issues.

## Contribution

The study identifies a novel mechanism by which CMV IE1 protein disrupts host PML–DISC1 interaction to impair neural progenitor proliferation.

## Key findings

- CMV IE1 protein interferes with host PML–DISC1 interaction, disturbing the Notch pathway in neural progenitor cells.
- CRISPR/Cas9 targeting IE1 rescues progenitor cell deficits in fetal brains with minimal off-target effects.
- IE1 disruption of PML–DISC1 interaction is a key driver of reduced neural progenitor proliferation in congenital CMV.

## Abstract

Congenital cytomegalovirus (CMV) infection is the most common perinatal infection, affecting up to 0.5% of infants. This elicits long-term disabilities that include neuropsychiatric manifestations, such as intellectual disability, microcephaly. Despite its high prevalence, the underlying mechanism of how congenitally acquired CMV infection causes brain pathology remain unknown. Here, we discovered the molecular interplay of key host (DISC1 and promyelocytic leukemia [PML]) and viral (immediate early 1 [IE1]) proteins within the neural progenitor cells, which underlay an attenuated neural progenitor proliferation in congenital CMV infection. Abolishing the viral IE1 protein by delivering IE1-targeting CRISPR/Cas9 to fetal brain rescued this progenitor cell deficit, a key pathology in congenital CMV infection. A selective targeting to a viral-specific protein by the CRISPR/Cas9 system is minimal in off-target effects. We further observed that CMV-encoded IE1 protein interferes with host PML–DISC1 interaction, resulting in disturbance of the Notch pathway in vitro and in embryonic brains. Therefore, we believe that a pivotal role of IE1 in an attenuated neural progenitor proliferation in the developing cortex through its interfering with interaction between host DISC1 and PML proteins.