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Activation of innate immune defense mechanisms contributes to polyomavirus BK-associated nephropathy

Andrea Ribeiro1, Markus Wörnle, Nasim Motamedi

  • 1Medizinische Poliklinik Campus Innenstadt, Klinikum der LMU, Munich, Germany.

Kidney International
|September 16, 2011
PubMed

Insights

Polyomavirus-associated nephropathy (PVAN) in kidney transplants activates Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) innate immune sensors. This response involves proinflammatory cytokine and chemokine expression, contributing to antiviral defense.

Area of Science:

  • Immunology
  • Nephrology
  • Virology

Background:

  • Polyomavirus-associated nephropathy (PVAN) is a major cause of kidney transplant failure.
  • The antiviral responses of renal tubular epithelium in PVAN are not fully understood.

Purpose of the Study:

  • To investigate the activation of viral DNA and double-stranded RNA (dsRNA) sensors, specifically Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I), in kidney allografts with PVAN.
  • To elucidate the role of these sensors in the innate immune response to BK virus infection in human collecting duct cells.

Main Methods:

  • Analysis of kidney allograft biopsy samples from PVAN patients using immunofluorescence and mRNA expression analysis.
  • In vitro studies using human collecting duct cells stimulated with poly(I:C), cytokines, or BK virus infection.
  • Assessment of TLR3 and RIG-I activation and downstream inflammatory gene expression.
  • Use of siRNA to block TLR3 activation.

Main Results:

  • TLR3, but not RIG-I, mRNA was upregulated in tubulointerstitial lesions of PVAN biopsies.
  • BK virus and TLR3 signals were detected in epithelial cells of distal cortical tubules and collecting ducts.
  • In vitro, poly(I:C) and BK virus infection activated TLR3 and RIG-I, leading to increased expression of cytokines, chemokines, and IFN-β.
  • TLR3 activation was crucial for the inflammatory response, as confirmed by siRNA blockade.
  • BK virus infection induced an antiviral response with TLR3 and RIG-I upregulation, but without inflammasome activation.

Conclusions:

  • PVAN involves the activation of innate immune defense mechanisms, particularly through TLR3 in the renal tubular epithelium.
  • TLR3 plays a significant role in the antiviral and anti-inflammatory response to BK virus in kidney allografts.
  • The study identifies TLR3 as a key mediator in the pathogenesis of PVAN, contributing to the expression of proinflammatory mediators.

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