01952nas a2200337   4500000000100000000000100001008004100002260001500043653001500058653002000073653000800093653002700101653002100128653001200149653002800161653001500189100002400204700002100228700002900249700002500278700001700303700002200320700001700342700002000359245011300379856004700492300000800539490000700547520104600554022001401600       2025                            d  c2025-11-0510aAstrocytes10abrain organoids10aCNS10aCentral Nervous System10aImmunometabolism10aNeurons10aQuantitative proteomics10aStem cells1 aPamela E. Capendale1 aAnoop T. Ambikan1 aInés García-Rodríguez1 aRenata Vieira de Sá1 aDasja Pajkrt1 aKatja C. Wolthers1 aUjjwal Neogi1 aAdithya Sridhar00aParechovirus-3 infection disrupts immunometabolism and leads to glutamate excitotoxicity in neural organoids  uhttps://doi.org/10.1007/s00018-025-05926-z  a3820 v823 aParechovirus 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.  a1420-9071