ABSTRACT
Background: JC polyomavirus (JCPyV) is reactivated in approximately 20% of renal transplant recipients, and it may rarely cause JCPyV-associated nephropathy (JCPyVAN). Whereas progressive multifocal leukoencephalopathy of the brain is caused by rearranged neurotropic JCPyV, little is known about viral sequence variation in JCPyVAN owing to the rarity of this condition. Methods: Using single-molecule real-time sequencing, characterization of full-length JCPyV genomes in urine and plasma samples from 1 patient with JCPyVAN and 20 stable renal transplant recipients with JCPyV viruria was attempted. Sequence analysis of JCPyV strains was performed, with emphasis on the noncoding control region, the major capsid protein gene VP1, and the large T antigen gene. Results: Exclusively archetype strains were identified in urine from the patient with JCPyVAN. Full-length JCPyV sequences were not retrieved from plasma. Archetype strains were found in urine samples from 19 stable renal transplant recipients, with JCPyV quasispecies detected in 5 samples. In a patient with minor graft dysfunction, a strain with an archetype-like noncoding cont rol region was discovered. Individual point mutations were detected in both VP1 and large T antigen genes. Conclusions: Archetype JCPyV was dominant in the patient with JCPyVAN and in stable renal transplant recipients. Archetype rather than rearranged JCPyV seems to drive the pathogenesis of JCPyVAN.
Subject(s)
JC Virus/pathogenicity , Kidney Diseases/virology , Kidney Transplantation/adverse effects , Leukoencephalopathy, Progressive Multifocal/virology , Polyomavirus Infections/virology , Tumor Virus Infections/virology , Adolescent , Adult , Aged , Child, Preschool , Humans , JC Virus/genetics , JC Virus/isolation & purification , Middle Aged , Transplant Recipients , Young AdultABSTRACT
The temporal activity and gene expression of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMP) were investigated in a rat model of chronic allograft nephropathy. Gelatinolytic activity of MMP-2 and -9 were demonstrated by zymography, and MMP-2,-9 and TIMP-3 mRNA by in situ hybridization. The generation of fibrosis was determined as total collagen content/DNA. Significantly more latent and active MMP-2, as well as latent MMP-9, were seen in allografts than in autografts. Intense MMP-2 mRNA expression was demonstrated in the allografts during the first 20 days after transplantation, located mainly in the interstitium of the kidney. In addition, some tubular cells expressed MMP-2 mRNA. After day 20, MMP-2 gene expression was faint. MMP-9 mRNA expression in allografts was located mainly in the glomerulus. TIMP-3 mRNA expression was downregulated in allografts. MMP-2, MMP-9 and TIMP-3 seem to play a critical role in the development of fibrosis in the renal allograft.
Subject(s)
Kidney Transplantation/pathology , Kidney Transplantation/physiology , Metalloproteases/metabolism , Animals , Collagen/biosynthesis , Fibrosis , Gene Expression , In Situ Hybridization , Male , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Metalloproteases/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Inbred BN , Rats, Inbred Strains , Tissue Inhibitor of Metalloproteinase-3/genetics , Tissue Inhibitor of Metalloproteinase-3/metabolism , Transplantation, Autologous , Transplantation, HomologousABSTRACT
Cytomegalovirus (CMV) infection has been shown to increase inflammation in rat liver allografts. In-vitro CMV has been shown to transactivate cyclo-oxygenase-2 (COX-2), while COX-2 plays a role in the CMV replication cycle. Our aim was to investigate the expression of COX-2 in liver allograft rejection and concomitant CMV infection. Expression of COX-2 was studied immunohistologically in rat liver allografts with or without rat CMV infection, in isografts, and in normal rat liver. There were small amounts of COX-2-positive mononuclear inflammatory cells in the normal liver and isografts. Acute rejection increased the amount of COX-2-expressing cells in the portal areas only, whereas concomitant CMV infection did this also in the sinusoid area. COX-2 may play a role in CMV infection in vivo as well. The possible role of COX-2 in the association between CMV infection and allograft rejection warrants further study.
