Prion protein alters viral control and enhances pathology after perinatal cytomegalovirus infection

Dubravka Karner, Daria Kvestak, Paola Kucan Brlic, Maja Cokaric Brdovcak, Berislav Lisnic, Ilija Brizic, Vanda Juranic Lisnic, Mijo Golemac, Jelena Tomac, Astrid Krmpotic, Esma Karkeni, Valentina Libri, Sebastien Mella, Giuseppe Legname, Hermann C. Altmeppen, Milena Hasan, Stipan Jonjic and Tihana Lenac Rovis ()
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Dubravka Karner: Center for Proteomics; Faculty of Medicine; University of Rijeka
Daria Kvestak: Center for Proteomics; Faculty of Medicine; University of Rijeka
Paola Kucan Brlic: Center for Proteomics; Faculty of Medicine; University of Rijeka
Maja Cokaric Brdovcak: Center for Proteomics; Faculty of Medicine; University of Rijeka
Berislav Lisnic: Center for Proteomics; Faculty of Medicine; University of Rijeka
Ilija Brizic: Center for Proteomics; Faculty of Medicine; University of Rijeka
Vanda Juranic Lisnic: Center for Proteomics; Faculty of Medicine; University of Rijeka
Mijo Golemac: University of Rijeka
Jelena Tomac: University of Rijeka
Astrid Krmpotic: University of Rijeka
Esma Karkeni: Université Paris Cité
Valentina Libri: Université Paris Cité
Sebastien Mella: Université Paris Cité
Giuseppe Legname: Scuola Internazionale Superiore di Studi Avanzati (SISSA)
Hermann C. Altmeppen: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf (UKE)
Milena Hasan: Université Paris Cité
Stipan Jonjic: Center for Proteomics; Faculty of Medicine; University of Rijeka
Tihana Lenac Rovis: Center for Proteomics; Faculty of Medicine; University of Rijeka

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Cytomegalovirus (CMV) infection poses risks to newborns, necessitating effective therapies. Given that the damage includes both viral infection of brain cells and immune system-related damage, here we investigate the involvement of cellular prion protein (PrP), which plays vital roles in neuroprotection and immune regulation. Using a murine model, we show the role of PrP in tempering neonatal T cell immunity during CMV infection. PrP-null mice exhibit enhanced viral control through elevated virus-specific CD8 T cell responses, leading to reduced viral titers and pathology. We further unravel the molecular mechanisms by showing CMV-induced upregulation followed by release of PrP via the metalloproteinase ADAM10, impairing CD8 T cell response specifically in neonates. Additionally, we confirm PrP downregulation in human CMV (HCMV)-infected fibroblasts, underscoring the broader relevance of our observations beyond the murine model. Furthermore, our study highlights how PrP, under the stress of viral pathogenesis, reveals its impact on neonatal immune modulation.

Date: 2024
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DOI: 10.1038/s41467-024-51931-4

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