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

Julia Manzetti1, Fabian H Weissbach1, Fabrice E Graf1

  • 1Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10, CH-4009 Basel, Switzerland.

Iscience
|June 30, 2020
PubMed

Insights

BK polyomavirus (BKPyV) infection disrupts mitochondria using its agnoprotein, promoting viral persistence and kidney transplant failure. This conserved mechanism also affects other polyomaviruses, impacting disease.

Area of Science:

  • Virology
  • Immunology
  • Cell Biology

Background:

  • Human polyomaviruses like BKPyV asymptomatically infect most people but can cause severe disease, particularly kidney transplant failure.
  • Despite immune responses, BKPyV persists and evades immune control, leading to urinary shedding and allograft complications.

Purpose of the Study:

  • To investigate the mechanism of BKPyV immune evasion and persistence.
  • To understand the role of BKPyV agnoprotein in viral replication and host cell manipulation.
  • To explore the conserved mechanisms of mitochondrial disruption by polyomaviruses.

Main Methods:

  • Analysis of BKPyV agnoprotein function in viral replication.
  • Investigation of mitochondrial network disruption and membrane potential changes.
  • Assessment of IRF3 translocation, interferon-beta expression, and mitophagy.
  • Examination of kidney transplant patient biopsies for viral markers and mitochondrial changes.

Main Results:

  • BKPyV agnoprotein disrupts mitochondrial networks and membrane potential during late replication.
  • Agnoprotein targets mitochondria via its amino-terminal and central domains, impairing IRF3 nuclear translocation and interferon-beta production.
  • Mitochondrial disruption promotes p62/SQSTM1-mediated mitophagy, contributing to viral persistence.
  • Viruses with impaired mitochondrial disruption show reduced replication and increased interferon-beta expression, but can be rescued by specific treatments.
  • Mitochondrial fragmentation and mitophagy are observed in kidney transplant patients with BKPyV nephropathy.
  • JC polyomavirus (JCPyV) and SV40 also disrupt mitochondrial networks, indicating a conserved mechanism.

Conclusions:

  • BKPyV agnoprotein-induced mitochondrial disruption is a key mechanism for immune evasion and viral persistence.
  • This conserved mechanism facilitates polyomavirus-associated diseases, including post-transplant nephropathy.
  • Targeting mitochondrial pathways may offer therapeutic strategies against BKPyV and related polyomaviruses.
Keywords:
Biological SciencesCell BiologyImmunologyVirology

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