# Parechovirus-3 infection disrupts immunometabolism and leads to glutamate excitotoxicity in neural organoids

## TL;DR

This study shows how Parechovirus-3 infection disrupts brain cell metabolism and causes harmful glutamate levels in neural organoids.

## Contribution

The study reveals novel insights into immunometabolic dysregulation and glutamate excitotoxicity caused by HPeV-3 in neural organoids.

## Key findings

- HPeV-3 infection alters immunometabolism in neural organoids.
- Elevated glutamate, LDH, and NfL levels confirm excitotoxicity and neuronal damage.
- Caspase signaling contributes to apoptosis following HPeV-3 infection.

## Abstract

Parechovirus ahumpari 3 (HPeV-3) is among the main agents causing severe neonatal neurological infections such as encephalitis and meningitis. However, the underlying molecular mechanisms and changes to the host cellular landscape leading to neurological disease has been understudied. Through quantitative proteomic analysis of HPeV-3 infected neural organoids, we identified unique metabolic changes following HPeV-3 infection that indicate immunometabolic dysregulation. Protein and pathway analyses showed significant alterations in neurotransmission and potentially, neuronal excitotoxicity. Elevated levels of extracellular glutamate, lactate dehydrogenase (LDH), and neurofilament light (NfL) confirmed glutamate excitotoxicity to be a key mechanism contributing to neuronal toxicity in HPeV-3 infection and can lead to apoptosis induced by caspase signaling. These insights are pivotal in delineating the metabolic landscape following severe HPeV-3 CNS infection and may identify potential host targets for therapeutic interventions.

The online version contains supplementary material available at 10.1007/s00018-025-05926-z.