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

• Published in: Nature communications Vol. 15; no. 1; pp. 7754 - 17
• Main Authors: Karner, Dubravka, Kvestak, Daria, Kucan Brlic, Paola, Cokaric Brdovcak, Maja, Lisnic, Berislav, Brizic, Ilija, Juranic Lisnic, Vanda, Golemac, Mijo, Tomac, Jelena, Krmpotic, Astrid, Karkeni, Esma, Libri, Valentina, Mella, Sebastien, Legname, Giuseppe, Altmeppen, Hermann C., Hasan, Milena, Jonjic, Stipan, Lenac Rovis, Tihana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/31; 13/51; 14/19; 38/88; 38/91; 631/1647/334/1874/345; 631/326/596/1553; 64/60; 692/4017; 692/420/254; 692/699; 82/29; 82/83; ADAM10 Protein - genetics; ADAM10 Protein - metabolism; Animal models; Animals; Animals, Newborn; Brain damage; Brain injury; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cytomegalovirus; Cytomegalovirus - immunology; Cytomegalovirus Infections - immunology; Cytomegalovirus Infections - virology; Disease Models, Animal; Female; Fibroblasts - metabolism; Fibroblasts - virology; Humanities and Social Sciences; Humans; Immune system; Immunomodulation; Immunoregulation; Infections; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; multidisciplinary; Neonates; Neuroprotection; Pathogenesis; Pathology; Prion protein; Prion Proteins - genetics; Prion Proteins - metabolism; Proteins; Science; Science (multidisciplinary); Viral infections
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51931-4

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. The role of cellular prion protein (PrP) during CMV infection in newborns is not entirely clear. Here, the authors show that CMV-induced PrP release mediated by ADAM10 shedding impairs the neonatal antiviral response in mice by compromising CD8 T-cells leading to higher viral titers and more severe disease outcome.