BK Polyomavirus Evades Innate Immune Sensing by Disrupting the Mitochondrial Network and Promotes Mitophagy

Julia Manzetti; Fabian H. Weissbach; Fabrice E. Graf; Gunhild Unterstab; Marion Wernli; Helmut Hopfer; Cinthia B. Drachenberg; Christine Hanssen Rinaldo; Hans H. Hirsch

iScience (Jul 2020)

BK Polyomavirus Evades Innate Immune Sensing by Disrupting the Mitochondrial Network and Promotes Mitophagy

Julia Manzetti,
Fabian H. Weissbach,
Fabrice E. Graf,
Gunhild Unterstab,
Marion Wernli,
Helmut Hopfer,
Cinthia B. Drachenberg,
Christine Hanssen Rinaldo,
Hans H. Hirsch

Affiliations

Julia Manzetti: Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10, CH-4009 Basel, Switzerland
Fabian H. Weissbach: Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10, CH-4009 Basel, Switzerland
Fabrice E. Graf: Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10, CH-4009 Basel, Switzerland
Gunhild Unterstab: Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10, CH-4009 Basel, Switzerland
Marion Wernli: Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10, CH-4009 Basel, Switzerland
Helmut Hopfer: Institute for Pathology, University Hospital Basel, Basel, Switzerland
Cinthia B. Drachenberg: Departments of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
Christine Hanssen Rinaldo: Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway; Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
Hans H. Hirsch: Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10, CH-4009 Basel, Switzerland; Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland; Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland; Corresponding author

Journal volume & issue: Vol. 23, no. 7
p. 101257

Abstract

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Summary: Immune escape contributes to viral persistence, yet little is known about human polyomaviruses. BK-polyomavirus (BKPyV) asymptomatically infects 90% of humans but causes premature allograft failure in kidney transplant patients. Despite virus-specific T cells and neutralizing antibodies, BKPyV persists in kidneys and evades immune control as evidenced by urinary shedding in immunocompetent individuals. Here, we report that BKPyV disrupts the mitochondrial network and membrane potential when expressing the 66aa-long agnoprotein during late replication. Agnoprotein is necessary and sufficient, using its amino-terminal and central domain for mitochondrial targeting and network disruption, respectively. Agnoprotein impairs nuclear IRF3-translocation, interferon-beta expression, and promotes p62/SQSTM1-mitophagy. Agnoprotein-mutant viruses unable to disrupt mitochondria show reduced replication and increased interferon-beta expression but can be rescued by type-I interferon blockade, TBK1-inhibition, or CoCl2-treatment. Mitochondrial fragmentation and p62/SQSTM1-autophagy occur in allograft biopsies of kidney transplant patients with BKPyV nephropathy. JCPyV and SV40 infection similarly disrupt mitochondrial networks, indicating a conserved mechanism facilitating polyomavirus persistence and post-transplant disease.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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