Pathogenic Old World Hantaviruses Infect Renal Glomerular and Tubular Cells and Induce Disassembling of Cell-to-Cell Contacts

Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Journal of Virology (Impact Factor: 4.44). 07/2011; 85(19):9811-23. DOI: 10.1128/JVI.00568-11
Source: PubMed


Viral hemorrhagic fevers are characterized by enhanced permeability. One of the most affected target organs of hantavirus-induced
hemorrhagic fever with renal syndrome is the kidney, and an infection often results in acute renal failure. To study the underlying
cellular effects leading to kidney dysfunction, we infected human renal cell types in vitro that are critical for the barrier functions of the kidney, and we examined kidney biopsy specimens obtained from hantavirus-infected
patients. We analyzed the infection and pathogenic effects in tubular epithelial and glomerular endothelial renal cells and
in podocytes. Both epithelial and endothelial cells and podocytes were susceptible to hantavirus infection in vitro. The infection disturbed the structure and integrity of cell-to-cell contacts, as demonstrated by redistribution and reduction
of the tight junction protein ZO-1 and the decrease in the transepithelial resistance in infected epithelial monolayers. An
analysis of renal biopsy specimens from hantavirus-infected patients revealed that the expression and the localization of
the tight junction protein ZO-1 were altered compared to renal biopsy specimens from noninfected individuals. Both tubular
and glomerular cells were affected by the infection. Furthermore, the decrease in glomerular ZO-1 correlates with disease
severity induced by glomerular dysfunction. The finding that different renal cell types are susceptible to hantaviral infection
and the fact that infection results in the breakdown of cell-to-cell contacts provide useful insights in hantaviral pathogenesis.

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    • "The clinical picture in NE includes acute kidney injury (AKI), thrombocytopenia, proteinuria and hematuria caused by tubular and glomerular involvement [12]. Both renal tubular and glomerular cells are affected by infection that leads to breakdown of cell-to cell contacts [13]. Therefore, the urinary sediment of patients with hantavirus infection contains tubular cells, with enlarged nucleoli, that are positive for hantavirus antigen [14]–[16]. "
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    ABSTRACT: Background Puumala virus (PUUV) is the most important hantavirus species in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute renal injury (AKI) with thrombocytopenia and frequently gastrointestinal symptoms. Methods 456 patients with serologically and clinically confirmed NE were investigated at time of follow-up in a single clinic. The course of the NE was investigated using medical reports. We identified patients who had endoscopy with intestinal biopsy during acute phase of NE. Histopathological, immunohistochemical and molecular analyses of the biopsies were performed. Results Thirteen patients underwent colonoscopy or gastroscopy for abdominal pain, diarrhea, nausea and vomiting during acute phase of NE. Immunohistochemistry (IHC) revealed PUUV nucleocapsid antigen in 11 biopsies from 8 patients; 14 biopsies from 5 patients were negative for PUUV nucleocapsid antigen. IHC localized PUUV nucleocapsid antigen in endothelial cells of capillaries or larger vessels in the lamina propria. Rate of AKI was not higher and severity of AKI was not different in the PUUV-positive compared to the PUUV-negative group. All IHC positive biopsies were positive for PUUV RNA using RT-PCR. Phylogenetic reconstruction revealed clustering of all PUUV strains from this study with viruses previously detected from the South-West of Germany. Long-term outcome was favorable in both groups. Conclusions In patients with NE, PUUV nucleocapsid antigen and PUUV RNA was detected frequently in the intestine. This finding could explain frequent GI-symptoms in NE patients, thus demonstration of a more generalized PUUV infection. The RT-PCR was an effective and sensitive method to detect PUUV RNA in FFPE tissues. Therefore, it can be used as a diagnostic and phylogenetic approach also for archival materials. AKI was not more often present in patients with PUUV-positive IHC. This last finding should be investigated in larger numbers of patients with PUUV infection.
    PLoS ONE 05/2014; 9(5):e98397. DOI:10.1371/journal.pone.0098397 · 3.23 Impact Factor
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    • "Hantaviruses can infect a variety of cell types, including endothelial cells, tissue macrophages, dendritic cells (DC) and renal tubular cells (Krautkramer et al. 2011; Markotic et al. 2007; Pensiero et al. 1992; Raftery et al. 2002). Infection of endothelial cells induces production of numerous cytokines, including monocyte chemoattractant protein (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES) and IFNγ-induced protein 10 (IP-10) (Sundstrom et al. 2001). "
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    ABSTRACT: Viral hemorrhagic diseases are a group of systemic viral infections with worldwide distribution and are significant causes of global mortality and morbidity. The hallmarks of viral hemorrhagic fevers are plasma leakage, thrombocytopenia, coagulopathy and hemorrhagic manifestations. The molecular mechanisms leading to plasma leakage in viral hemorrhagic fevers are not well understood. A common theme has emerged in which a complex interplay between pathogens, host immune response, and endothelial cells leads to the activation of endothelial cells and perturbation of barrier integrity. In this article, two clinically distinct viral hemorrhagic fevers caused by dengue viruses and hantaviruses are discussed to highlight their similarities and differences that may provide insights into the pathogenesis and therapeutic approach.
    Cell and Tissue Research 03/2014; 355(3). DOI:10.1007/s00441-014-1841-9 · 3.57 Impact Factor
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    • "It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. Pathogenic hantaviruses bind to αvβ3 integrins and markedly increase the permeability of endothelial cells in response to VEGF, whereas non-pathogenic hantaviruses have not such effect [13,14,15,16]. Specifically, pathogenic hantaviruses induce increased phosphorylation of the VEGFR2 in infected endothelial cells, which leads to phosphorylation, internalization and degradation of vascular endothelial cadherin (VE-cadherin), predominant structural component of the adherens junctions, resulting in paracellular permeability and microvascular leak [17]. "
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    ABSTRACT: The levels of vascular endothelial growth factor-A (VEGF) were estimated in 102 serum samples from 63 hospitalized Greek patients with hemorrhagic fever with renal syndrome (HFRS) caused by Dobrava/Belgrade virus. Significantly higher VEGF levels were seen in the severe when compared with non-severe cases (mean values 851.96 pg/mL and 326.75 pg/mL, respectively; p = 0.003), while a significant difference was observed among groups based on the day after the onset of illness. In both severe and non-severe cases, VEGF peaked in the second week of illness; however, elevation of VEGF in the severe cases started later and remained high until convalescence, suggesting that the role of VEGF was associated with repair of vascular damage rather than with increased permeability.
    Viruses 12/2013; 5(12):3109-3118. DOI:10.3390/v5123109 · 3.35 Impact Factor
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