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

doi:10.1016/j.isci.2020.101257

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

iScience. 2020 Jul 24;23(7):101257. doi: 10.1016/j.isci.2020.101257. Epub 2020 Jun 10.

Authors

Julia Manzetti¹, Fabian H Weissbach¹, Fabrice E Graf¹, Gunhild Unterstab¹, Marion Wernli¹, Helmut Hopfer², Cinthia B Drachenberg³, Christine Hanssen Rinaldo⁴, Hans H Hirsch⁵

Affiliations

¹ Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10, CH-4009 Basel, Switzerland.
² Institute for Pathology, University Hospital Basel, Basel, Switzerland.
³ Departments of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴ 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.
⁵ 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. Electronic address: [email protected].

Abstract

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.

Keywords: Biological Sciences; Cell Biology; Immunology; Virology.