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Functional Consequences of Old World Hantavirus Infection in Human Renal Cells

Hägele, Stefan

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Abstract

Viral infections of the kidney, with severe clinical pictures, represent an ongoing threat. The hemorrhagic fever with renal syndrome (HFRS) is caused by several species of pathogenic Old World hantaviruses and is clinically characterized by cellular permeability disorders, leading to acute kidney injury. Previously, it was shown that podocytes and tubular epithelial cells, which play a key role in renal function, are permissive for hantaviruses and further, that the infection was causing a disruption of cell-to-cell contacts correlating with the disease severity. Up until today, the renal-specific pathogenesis mechanisms of hantavirus infections, leading to the cellular leakage, are not well understood. In this study, functional and morphological consequences of hantavirus infection are examined in human renal cells and compared to African green monkey Vero E6 cells, which are commonly used to study hantaviruses. Analysis of podocytes and tubular epithelium in human renal biopsies of hantavirus-infected patients revealed distinct morphological changes known to be involved in functional disorders of various kidney diseases. To investigate how hantaviruses cause cellular disorders, the effects were further examined using in vitro experiments. Infections of podocytes and tubular epithelial cells with either Hantaan (HTNV) or Puumala virus (PUUV) caused cytoskeletal rearrangements in combination with an impairment of adhesion and motility capacity. The nucleocapsid (N) protein was associated with the actin cytoskeleton and, in addition to that, the integrity of filamentous (F-) actin was crucial for viral release. Furthermore, the transfection of podocytes revealed that the expression of N protein alone was sufficient to impair cellular functions. Soluble factors contributing to the cellular disturbances were neither detected in the supernatant of in vitro infected podocytes nor in the serum of hantavirus-infected patients, indicating direct effects of infection on renal cells. According to the severity of the clinical picture, the in vitro effects of hantaviral infections and N protein expression were more pronounced for HTNV than for PUUV. In contrast, the hantavirus infections were clearly different in Vero E6 cells and no functional consequences and actin involvement were observed, demonstrating the importance of choosing relevant cell culture models. These results demonstrate that hantavirus-induced morphological and functional injuries are species- and cell type-specific. The association of N protein with actin and its involvement in the viral release might play a role in the underlying mechanism, leading to functional impairment and cell-to-cell contact disruption. Moreover, the N protein is identified to be a pathogenicity factor of Old World hantaviruses. Conclusively, these findings might contribute to the understanding of the pathogenesis mechanisms leading to the clinical picture of hantavirus-induced acute renal failure.

Item Type: Dissertation
Supervisor: Frings, Prof. Dr. Stephan
Date of thesis defense: 14 February 2018
Date Deposited: 05 Mar 2018 07:58
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
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