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

Abstract

Polyomavirus-associated nephropathy due to BK virus infection (BKVAN) is recognized as an important cause of significant kidney transplant dysfunction often leading to renal graft loss. The activation of innate immune defense mechanisms during BKVAN is still poorly understood and an altered regulation of inflammatory mediators by resident kidney cells upon viral infection can be expected to contribute to the onset and progression of disease. TNFα interacting with its receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), is largely accepted to be involved in viral responses, exhibiting both proinflammatory and immunosuppressive effects. Our aim was to examine the expressions of TNFα and TNFR1 and 2 in human collecting duct epithelial cells (HCDC) after infection with BKV as well as to study the effect of TNFα and poly(I:C), a synthetic analog of viral RNA, on the expressions of TNF receptors and proinflammatory cytokines and chemokines in HCDC. Quantitative RT-PCR analyses showed a downregulation of TNFα and an upregulation of both TNFR1 and 2 upon exposure of HCDC to the BK virus. TNFα stimulation induced the expressions of IL-6, IL-8, RANTES, and TNFR2. Poly(I:C) upregulated the expressions of both TNFR1 and TNFR2, a response that could be effectively blocked by siRNA to TLR3 and RIG-I, two double-stranded (ds) RNA receptors of the innate immune system. Poly(I:C)-dependent expression of TNFR2 but not TNFR1 was enhanced by TNFα. Taken together, our results suggest an involvement of TNF/TNFR system in virus-associated nephropathy.

IL28B rs12979860 genotype as a predictor marker of progression to BKVirus Associated nephropathy, after kidney transplantation

“…Recently, studies by Ribiero et al . 23 , 24 have described a range of mechanisms by which the innate immune system is involved in BKV infection. They described an upregulation of the TLR3 in renal biopsies with BKVAN.…”

“…Briefly, BKV− dsRNA is recognized by the TLR3 (specific dsRNA intracellular sensor, highly expressed in renal epithelial cells) which triggers the activation of the NF-ƙB and subsequently the production of IFNs, IL-6, IL-8 23 . They also described the involvement of the TNFα/TNF receptor system (induce tubular expression of IL-6 and IL-8 - relevant in BKVAN) in host’s BKV antiviral response 24 . Produced by most renal cells, in an inflammatory setting, TNFα, is relevant for both antiviral activity and immune modulation.…”

“…It is presumed that detachment, rather than cell lysis, might explain the absence of significant inflammation, despite the high level of BKV replication in the urothelium. Moreover, new information regarding BKV− specific immunity kinetics 22 , as well as activation of the antiviral state by the polyomavirus T antigen, is now available, providing testable hypotheses on how BKV replication may cause severe disease in humans, and the response of innate immune activation after viral infection 23 , 24 . In particular, Nicholas et al .…”

Viruses in transplantology

“…26 Further research of BKV -specific immune response is necessary, as it may lead to the development of effective treatments and vaccines (FIGURE 2). 27,28 After allograft loss due to BKVAN, retransplantation is possible unless the virus continues to replicate. Transplant nephrectomy of allografts lost due to BKVAN does not affect long --term treatment outcomes.…”

“…BKV may downregulate TNF -α and upregulate both TNF αR1 and TNF αR2 in human collecting duct epithelial cells. Such a response could be effectively blocked by small interfering RNA (siRNA) to toll -like receptor 1 (TLR1) and retinoic acid inducible gene -I (RIG -I), 2 double -stranded RNA receptors of the innate immune system 28. Abbreviations: IL, interleukin; RANTES, regulated on activation, normal T -cell expressed and secreted TNFα…”