# Mild SARS-CoV-2 maternal infection in mice induces transient offspring neurodevelopmental aberrance

## TL;DR

Mild SARS-CoV-2 infection in pregnant mice causes temporary brain gene changes in offspring, but no lasting brain structure or behavior issues.

## Contribution

This study is the first to show that mild maternal SARS-CoV-2 infection can transiently affect offspring brain gene expression without severe maternal symptoms.

## Key findings

- Mild maternal SARS-CoV-2 infection caused placental inflammation and fetal brain gene expression changes.
- Offspring brain gene changes resolved by later childhood without affecting brain structure or behavior.
- Soluble factors from maternal respiratory infection mediate placental and fetal brain effects.

## Abstract

The rising global numbers of SARS-CoV-2 infections highlight the need to assess potential neurodevelopmental and psychiatric impact in children born to infected mothers. Human cohorts have provided conflicting conclusions, while mouse studies have focused on moderate-to-severe infection despite most infections in pregnant women being mild or asymptomatic. Our study shows that mild, respiratory tract–restricted SARS-CoV-2 infection in pregnant mice was sufficient to cause placental inflammation and transient changes in offspring brain gene expression, without altering gross brain structure or behavior under our experimental conditions. These findings suggest that soluble factors induced by maternal respiratory infection mediate placental inflammation and changes in offspring brain gene expression during the fetal and neonatal periods, which resolve in later childhood.

Maternal viral infection during pregnancy has been identified as a risk factor for psychiatric disorders and neurodevelopmental abnormalities in offspring. With cumulative SARS-CoV-2 infections now numbering in the hundreds of millions globally, there is a need to evaluate the effects of maternal SARS-CoV-2 infection on offspring brain development and behavior. We developed a mouse model of mild COVID-19 during pregnancy in which SARS-CoV-2 infection is restricted to the respiratory tract. Infected mothers did not show weight loss or changes in litter size, but did exhibit detectable local and systemic immune responses, including placental inflammation. Characterization of the offspring’s cerebral cortex revealed transcriptomic changes in the fetus at E15 and on postnatal day 5 (P5), but no gross alterations in cytoarchitecture, synaptic density, or microglial abundance. We did not detect any significant changes in open-field or novel object recognition tests in P50 offspring born to SARS-CoV-2-infected dams. These findings suggest that mild maternal respiratory SARS-CoV-2 infection induces soluble factors that mediate placental inflammation and transient cerebral cortex alterations in offspring that resolve by later childhood.