BK polyomavirus evades innate immune sensing by disrupting the mitochondrial network and promotes mitophagy

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, 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.