The epithelium is a critical barrier for pathogens, and entering the target tissue requires strategies to disrupt the integrity of cell-to-cell contacts. The infection of polarized monolayers is often directly linked to the pathogenesis of disease. The clinical picture of human hantaviral infections differs between Old and New World hantavirus. They may vary in the target organ, in which the infection predominantly manifests. An infection with Old World hantaviruses often leads to acute renal failure with massive proteinuria (1
). In recent years reports of cases with pulmonary involvement in Old World hantavirus infection were reported, as well as involvement of other organs (28
). The understanding of the susceptibility of human cells for hantavirus infection and the effects of replication on the host cell is crucial for the study of the underlying mechanism of hantaviral pathogenesis. However, the underlying mechanisms of renal dysfunction in HFRS are not yet well understood. The productive infection of renal cells may cause direct effects induced by the viral replication or infection may be responsible for the attack of infected cells by invading immune cells (1
). The function of the kidney depends on the glomerular layers (fenestrated endothelium, podocytes, and basement membrane) and the integrity of the tubular epithelium (12
). The endothelium of glomerular capillaries differs with its fenestrae from other vascular endothelia that are characterized by tight junction formation, but the fenestrated endothelium works as a molecular filter via its glycocalyx. Podocytes form the barrier via the interdigitated foot processes and their connecting slit diaphragms, specialized multiprotein complexes that share similarities with tight and adherens junctions. A mild dysfunction of the glomerular barrier function can be covered by tubular reabsorption. However, glomerular together with tubular disorder results in proteinuria (11
). Our results from cell culture experiments and renal biopsy specimens showed that both systems, glomerular and tubular, show junctional remodeling and may explain the clinical picture of hantavirus-induced acute renal failure that is characterized by massive proteinuria.
Hemorrhagic fever viruses often exert a pronounced tropism for organ-specific epithelia and endothelia. The Nipah virus infects preferentially endothelial cells of small blood and lymphatic vessels corresponding to the expression pattern of the receptor ephrinB2 (54
). The measles virus is able to infect respiratory epithelium, dermal capillary, and microvascular endothelial cells in the brain (2
). Studies on dengue virus infection demonstrated viral antigen in endothelial cells of the liver, spleen, and alveoli (31
). In vitro
studies concerning the pathogenesis of viral hemorrhagic disease often make use of human endothelial cells of the umbilical vein (HUVEC). However, endothelial cells of different organs are heterogeneous, since they are specialized for the function in the respective tissue. They exert a typical morphology and protein expression profile (3
). An infection with Old World hantaviruses causes HFRS, and the infection with New World hantaviruses leads to HPS. The fenestrated glomerular endothelium of the kidney differs significantly from the continuous endothelium of other organs (24
). The well-defined endothelial specialization and heterogeneity are not only apparent in the tropism of pathogens, many human vascular diseases are limited to distinct types of vessels, e.g., autoimmune diseases that mainly manifest in the kidney (34
). The strong association between disease and cell type demands the investigation of the underlying molecular pathomechanism in a cell culture model relating to the relevant target organ (79
We have shown that the hantavirus receptor integrin αV
is expressed on tubular and glomerular cells of the human kidney and that podocytes and glomerular endothelial and tubular epithelial cells are permissive to infection and release infectious particles. In contrast to the comparable replication kinetics of HTNV in epithelial cells and podocytes, the virus infects the glomerular endothelial monolayer much more efficiently. The infection of the glomerular endothelium may allow the entry of the hantavirus into the kidney with subsequent infection of podocytes and tubular cells. The expression of the hantaviral coreceptor CD55 on different renal cell types may also play a role in the susceptibility (8
). An analysis of the impact of infection on the integrity of the cell-to-cell contacts revealed structural alterations in tubular and glomerular cells. We also demonstrated the presence of hantaviral antigen in the kidney and the disruption of junctional structures in biopsy specimens of infected patients. The remodeling affects tight junctions of tubular epithelial cells and the glomerular slit diaphragm between the foot processes of podocytes. Further investigations will focus on possible mechanisms that are either direct, since the viral replication could induce a redistribution of junctional proteins, or the disruption of tight junctions could be a consequence of the effects of cytokines. The induction of the innate immune system by hantavirus infection leads to the secretion of cytokines that may be involved in the signaling cascade controlling epithelial and endothelial permeability (10
). A stimulation of hantavirus-infected HUVECs with TNF-α or vascular endothelial growth factor (VEGF) results in a higher permeability than a stimulation of uninfected monolayers (21
). VEGF and VEGF receptors 1 and 2 are also expressed in renal cells. Since VEGF plays a crucial role in the maintenance of the filtration barrier (16
), the infection with hantavirus could enhance the sensitivity for VEGF in renal cells and increase the permeability the same way as in HUVECs. The role for VEGF in virus-induced renal dysfunction was shown in HIV-associated nephropathy, where the infection of podocytes with HIV induces the expression of VEGF and VEGFR2, leading to podocyte dedifferentiation and disease (38
). The histopathological changes in hantavirus infection represent mild tubular interstitial changes and moderate interstitial infiltration of mononuclear cells. However, analyzing the cell-to-cell contacts revealed that the hantavirus-induced acute renal failure differs from interstitial nephritis of nonhantaviral origin that displays no redistribution of junctional proteins.
To summarize, we could demonstrate that renal cells, which are responsible for the function of the kidney, are susceptible to the infection with hantavirus and lose their barrier function by specific remodeling of the structure of cell-to-cell contacts. The disorganization affects both the tubular and the glomerular apparatus, leading to the hantavirus-specific clinical picture that is characterized by renal failure with massive proteinuria.