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

Abstract

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.

Japanese Encephalitis Virus Disrupts Cell-Cell Junctions and Affects the Epithelial Permeability Barrier Functions

“…RNA viruses such as vesicular stomatitis virus, influenza virus and rotavirus have been shown to influence the permeability barrier functions of epithelial cells with or without cytopathic effects at later stages of infection [54], [55]. Kidney biopsies from patients infected with highly pathogenic hantaviruses revealed altered expression and localization of ZO-1 which correlated with disease severity [56]. In many cases, viral proteins responsible for affecting TJ functions have been identified.…”

Glomerular Proteinuria Predicts the Severity of Acute Kidney Injury in Puumala Hantavirus-Induced Tubulointerstitial Nephritis

“…However, even in the case of massive transient proteinuria, the associated glomerular lesions with respect to adhesion molecules, cytokines, and cell infiltration remain negligible [21] . The hantaviruses can infect not only vascular endothelial cells, but also glomerular endothelial cells, tubular cells, and podocytes, disrupting the cell-to-cell contacts in all of these cell types [42] . Indeed, in electron microscopic studies, fusion of podocyte foot processes was already found in 1978 [43,44] .…”

Viral disruption of the blood–brain barrier

“…For example, HCV infection promotes expression of vascular endothelial growth factor, which alters tight junction integrity and polarity of hepatocytes [89]. Hemorrhagic hantavirus infection of renal epithelial and endothelial cells results in redistribution and reduction in tight junction protein ZO-1 and reduced transepithelial electrical resistance [90]. Dengue virus infection increases vascular permeability, particularly in severe dengue hemorrhagic fever and dengue shock syndrome.…”