Monkeypox virus spreads from cell-to-cell and leads to neuronal death in human neural organoids

Isabel Schultz-Pernice, Amal Fahmi, Francisco Brito, Matthias Liniger, Yen-Chi Chiu, Teodora David, Blandina I. Oliveira Esteves, Antoinette Golomingi, Beatrice Zumkehr, Markus Gerber, Damian Jandrasits, Roland Züst, Selina Steiner, Carlos Wotzkow, Fabian Blank, Olivier B. Engler, Artur Summerfield, Nicolas Ruggli, David Baud and Marco P. Alves ()
Additional contact information
Isabel Schultz-Pernice: Bern and Mittelhäusern
Amal Fahmi: Bern and Mittelhäusern
Francisco Brito: Bern and Mittelhäusern
Matthias Liniger: Bern and Mittelhäusern
Yen-Chi Chiu: Lausanne University Hospital
Teodora David: Bern and Mittelhäusern
Blandina I. Oliveira Esteves: Bern and Mittelhäusern
Antoinette Golomingi: Bern and Mittelhäusern
Beatrice Zumkehr: Bern and Mittelhäusern
Markus Gerber: Bern and Mittelhäusern
Damian Jandrasits: University of Bern
Roland Züst: Swiss Federal Office for Civil Protection
Selina Steiner: University of Bern
Carlos Wotzkow: University of Bern
Fabian Blank: University of Bern
Olivier B. Engler: Swiss Federal Office for Civil Protection
Artur Summerfield: Bern and Mittelhäusern
Nicolas Ruggli: Bern and Mittelhäusern
David Baud: Lausanne University Hospital
Marco P. Alves: Bern and Mittelhäusern

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract In 2022-23, the world witnessed the largest recorded outbreak of monkeypox virus (MPXV). Neurological manifestations were reported alongside the detection of MPXV DNA and MPXV-specific antibodies in the cerebrospinal fluid of patients. Here, we analyze the susceptibility of neural tissue to MPXV using human neural organoids (hNOs) exposed to a clade IIb isolate. We report susceptibility of several cell types to the virus, including neural progenitor cells and neurons. The virus efficiently replicates in hNOs, as indicated by the exponential increase of infectious viral titers and establishment of viral factories. Our findings reveal focal enrichment of viral antigen alongside accumulation of cell-associated infectious virus, suggesting viral cell-to-cell spread. Using an mNeonGreen-expressing recombinant MPXV, we confirm cell-associated virus transmission. We furthermore show the formation of beads in infected neurites, a phenomenon associated with neurodegenerative disorders. Bead appearance precedes neurite-initiated cell death, as confirmed through live-cell imaging. Accordingly, hNO-transcriptome analysis reveals alterations in cellular homeostasis and upregulation of neurodegeneration-associated transcripts, despite scarcity of inflammatory and antiviral responses. Notably, tecovirimat treatment of MPXV-infected hNOs significantly reduces infectious virus loads. Our findings suggest that viral disruption of neuritic transport drives neuronal degeneration, potentially contributing to MPXV neuropathology and revealing targets for therapeutic intervention.

Date: 2025
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DOI: 10.1038/s41467-025-61134-0

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