Identification of CCZ1 as an essential lysosomal trafficking regulator in Marburg and Ebola virus infections

Vanessa Monteil, Hyesoo Kwon, Lijo John, Cristiano Salata, Gustav Jonsson, Sabine U. Vorrink, Sofia Appelberg, Sonia Youhanna, Matheus Dyczynski, Alexandra Leopoldi, Nicole Leeb, Jennifer Volz, Astrid Hagelkruys, Max J. Kellner, Stéphanie Devignot, Georg Michlits, Michelle Foong-Sobis, Friedemann Weber, Volker M. Lauschke, Moritz Horn, Heinz Feldmann, Ulrich Elling, Josef M. Penninger and Ali Mirazimi ()
Additional contact information
Vanessa Monteil: Karolinska Institute and Karolinska University Hospital, Department of Laboratory Medicine, Unit of Clinical Microbiology
Hyesoo Kwon: National Veterinary Institute
Lijo John: National Veterinary Institute
Cristiano Salata: University of Padova
Gustav Jonsson: Institute of Molecular Biotechnology of the Austrian Academy of Science
Sabine U. Vorrink: Karolinska Institutet
Sofia Appelberg: Public Health Agency of Sweden
Sonia Youhanna: Karolinska Institutet
Matheus Dyczynski: Acus Laboratories GmbH
Alexandra Leopoldi: Institute of Molecular Biotechnology of the Austrian Academy of Science
Nicole Leeb: Institute of Molecular Biotechnology of the Austrian Academy of Science
Jennifer Volz: Institute of Molecular Biotechnology of the Austrian Academy of Science
Astrid Hagelkruys: Institute of Molecular Biotechnology of the Austrian Academy of Science
Max J. Kellner: Institute of Molecular Biotechnology of the Austrian Academy of Science
Stéphanie Devignot: Karolinska Institute and Karolinska University Hospital, Department of Laboratory Medicine, Unit of Clinical Microbiology
Georg Michlits: Acus Laboratories GmbH
Michelle Foong-Sobis: Institute of Molecular Biotechnology of the Austrian Academy of Science
Friedemann Weber: Justus Liebig University
Volker M. Lauschke: Karolinska Institutet
Moritz Horn: Acus Laboratories GmbH
Heinz Feldmann: National Institutes of Health
Ulrich Elling: Institute of Molecular Biotechnology of the Austrian Academy of Science
Josef M. Penninger: Institute of Molecular Biotechnology of the Austrian Academy of Science
Ali Mirazimi: Karolinska Institute and Karolinska University Hospital, Department of Laboratory Medicine, Unit of Clinical Microbiology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Marburg and Ebola filoviruses are two of the deadliest infectious agents and several outbreaks have occurred in the last decades. Although several receptors and co-receptors have been reported for Ebola virus, key host factors remain to be elucidated. In this study, using a haploid cell screening platform, we identify the guanine nucleotide exchange factor CCZ1 as a key host factor in the early stage of filovirus replication. The critical role of CCZ1 for filovirus infections is validated in 3D primary human hepatocyte cultures and human blood-vessel organoids, both critical target sites for Ebola and Marburg virus tropism. Mechanistically, CCZ1 controls early to late endosomal trafficking of these viruses. In addition, we report that CCZ1 has a role in the endosomal trafficking of endocytosis-dependent SARS-CoV-2 infections, but not in infections by Lassa virus, which enters endo-lysosomal trafficking at the late endosome stage. Thus, we have identified an essential host pathway for filovirus infections in cell lines and engineered human target tissues. Inhibition of CCZ1 nearly completely abolishes Marburg and Ebola infections. Thus, targeting CCZ1 could potentially serve as a promising drug target for controlling infections caused by various viruses, such as SARS-CoV-2, Marburg, and Ebola.

Date: 2023
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DOI: 10.1038/s41467-023-42526-6

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