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

Abstract

Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic:polyribocytidylic acid (poly(I:C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct. In biopsies microdissected to isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA expression was found to be increased in PVAN. Collecting duct cells in culture expressed TLR3 intracellularly, and activation of TLR3 and RIG-I by poly(I:C) enhanced expression of cytokine, chemokine, and IFN-β mRNA. This inflammatory response could be specifically blocked by siRNA to TLR3. Finally, infection of the collecting duct cells with BK virus enhanced the expression of cytokines and chemokines. This led to an efficient antiviral immune response with TLR3 and RIG-I upregulation without activation of IL-1β or components of the inflammasome pathway. Thus, PVAN activation of innate immune defense mechanisms through TLR3 is involved in the antiviral and anti-inflammatory response leading to the expression of proinflammatory cytokines and chemokines.

Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion

“…In contrast to widely expressed Toll-like receptors or Rig-like helicases, the NLRP3/ASC/caspase-1 axis is restricted to antigenpresenting cells inside the kidney (25)(26)(27). We used clodronate liposome in WT mice or diphtheria toxin in CD11c DTRg mice to demonstrate that CaOx-induced intrarenal IL-1β secretion originated from the intrarenal network of interstitial mononuclear phagocytes, which includes several DC populations (28).…”

Links between coagulation, inflammation, regeneration, and fibrosis in kidney pathology

“…Immune activation is absolutely necessary to suppress BK virus replication and infection in kidney allografts. 97,98 The same applies to the control of Escherichia coli and other uropathogenic bacteria during bacterial pyelonephritis 99 ( Figure 2b). Inflammationmediated pathogen killing limits pathogen spreading to systemic infection, as it happens in TLR4-mutant mice.…”

BK virus infection activates the TNFα/TNF receptor system in Polyomavirus-associated nephropathy

“…Cell culture of human collecting duct epithelial cells Immortalized human cortical collecting duct epithelial cells (HCDC), provided by H. Debiec [23], were grown as described [5]. BKVAN of the cells was described previously [5].…”

“…These cytopathic changes are often associated with lysis of tubular epithelial cells, denudation of the basement membrane, and a strong interstitial inflammatory response, similar to the histopathological alterations seen in AR, which produces a treatment dilemma [4]. Renal epithelial cells, in particular those of collecting tubule origin, can behave like inflammatory cells and produce cytokines or chemokines relevant to viral disease-associated nephropathy [5]. The expressions of inflammatory mediators can be enhanced by nucleic acids originating directly from the viral genome or by viral dsRNA intermediately formed by most viruses during their replication cycle [6].…”