Pharmacological targeting of bunyavirus-induced synaptic impairment prevents neuronal hyperexcitability

Orthobunyaviruses are linked to a broad spectrum of neurological disorders. However, the molecular determinants governing bunyavirus neuropathogenesis remain poorly understood, precluding the identification of drugs able to alleviate virus-induced neuronal dysfunctions. Here, we show that the prevalent, yet neglected, orthobunyavirus Ťahyňa virus (TAHV) disrupts neuronal integrity and proteostasis in human cerebral organoids (hCO), significantly decreasing synaptic protein expression and density. Moreover, TAHV-induced synaptic remodeling is associated with perturbed local field potential in organotypic cultures of human post-mortem adult brain explants (OPAB) and higher expression of the metabotropic Glutamate receptor 1 (mGluR1) in mice in the absence of overt neurological disease or neuroinflammation. Using proteome-based network medicine, we identified gabapentin as a therapeutic candidate that restores neurotransmitter receptor levels back to baseline in mice, and prevents TAHV-induced hyperexcitability in OPAB. Together, our data highlights the underappreciated neuropathological potential of a neglected orthobunyavirus, that interferes with neural integrity and neurotransmission, while neuromodulatory interventions may help to preserve cerebral functions. his study reveals the neuropathologic potential of the neglected Tahyna virus, and presents a powerful pipeline to discover antivirals that target the consequences of an infection (disorder oriented) rather than the infection itself (viro-centric).

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Journal
Nature Communications
Published
2026-09-01
DOI
https://doi.org/10.1038/s41467-026-77284-8
Primary Topic
Viral Infections and Vectors
Type
article
Field-Weighted Citation Impact
0.00

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article

Pharmacological targeting of bunyavirus-induced synaptic impairment prevents neuronal hyperexcitability

Hem Chandra Jha, Barbara Gorda, Emma Partiot, François Delalande et al.
Nature Communications
Viral Infections and Vectors
article

Pharmacological targeting of bunyavirus-induced synaptic impairment prevents neuronal hyperexcitability

Hem Chandra Jha, Barbara Gorda, Emma Partiot, François Delalande, Diana Brychka, Gowrishankar Ganesh, Raphaël Gaudin, Sophie Colomb, Aurélie Hirschler, Corentin Bernou, Christine Carapito, Solange Desagher, Jules Bouget, Pramesh Sinha, Hamendra Singh Parmar, Vaishali Saini, Glaucia M. Almeida, Willy Lutz
article en

Abstract

Orthobunyaviruses are linked to a broad spectrum of neurological disorders. However, the molecular determinants governing bunyavirus neuropathogenesis remain poorly understood, precluding the identification of drugs able to alleviate virus-induced neuronal dysfunctions. Here, we show that the prevalent, yet neglected, orthobunyavirus Ťahyňa virus (TAHV) disrupts neuronal integrity and proteostasis in human cerebral organoids (hCO), significantly decreasing synaptic protein expression and density. Moreover, TAHV-induced synaptic remodeling is associated with perturbed local field potential in organotypic cultures of human post-mortem adult brain explants (OPAB) and higher expression of the metabotropic Glutamate receptor 1 (mGluR1) in mice in the absence of overt neurological disease or neuroinflammation. Using proteome-based network medicine, we identified gabapentin as a therapeutic candidate that restores neurotransmitter receptor levels back to baseline in mice, and prevents TAHV-induced hyperexcitability in OPAB. Together, our data highlights the underappreciated neuropathological potential of a neglected orthobunyavirus, that interferes with neural integrity and neurotransmission, while neuromodulatory interventions may help to preserve cerebral functions. his study reveals the neuropathologic potential of the neglected Tahyna virus, and presents a powerful pipeline to discover antivirals that target the consequences of an infection (disorder oriented) rather than the infection itself (viro-centric).

Nature Communications
Centre National de la Recherche Scientifique (FR), Devi Ahilya Vishwavidyalaya (IN), Université de Montpellier (FR), Institut Pluridisciplinaire Hubert Curien (FR), Centre Hospitalier Universitaire de Montpellier (FR), Laboratoire d'Informatique, de Robotique et de Microélectronique de Montpellier (FR), Institut de Recherche en Infectiologie de Montpellier (FR), Indian Institute of Technology Indore (IN), Université de Strasbourg (FR)
Arthritis National Research Foundation, Biogen, Human Frontier Science Program, National Research Foundation, Agence Nationale de la Recherche, Indo-French Centre for the Promotion of Advanced Research, Centre National de la Recherche Scientifique, Campus France, National Institutes of Health, National Institute of Allergy and Infectious Diseases
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