Mobilization of circulating endothelial progenitor cells correlates with the clinical course of hantavirus disease.

Infections with hemorrhagic fever viruses are characterized by increased permeability leading to capillary leakage. Hantavirus infection is associated with endothelial dysfunction, and the clinical course is related to the degree of vascular injury. Circulating endothelial progenitor cells (cEPCs) play a pivotal role in the repair of the damaged endothelium. Therefore, we analyzed the number of cEPCs and their mobilizing growth factors in patients suffering from hantavirus disease induced by infection with Puumala virus. The numbers of EPCs of 36 hantavirus-infected patients and age- and gender-matched healthy controls were analyzed by flow cytometry. Concentrations of cEPC-mobilizing growth factors in plasma were determined by enzyme-linked immunosorbent assay. Laboratory parameters were correlated with the number of cEPCs. In patients infected with hantavirus, the number of cEPCs was significantly higher than that in healthy controls. Levels of mobilizing cytokines were upregulated in patients, and the mobilization of cEPCs is paralleled with the normalization of clinical parameters. Moreover, higher levels of cEPCs correlated with higher serum albumin levels and platelet concentrations. Our data indicate that cEPCs may play a role in the repair of hantavirus-induced endothelial damage, thereby influencing the clinical course and the severity of symptoms.

No gender-related differences in the severity of nephropathia epidemica, Germany.

BACKGROUND: The number of cases of hantavirus disease caused by Puumala virus is increasing enormously in Germany within the last years. Men are overrepresented in hantavirus disease and differences in course and symptoms in relation to gender were reported from several countries. This study was conducted to define possible gender-specific risk factors and aspects of severity in hantavirus infections occurring in Germany. METHODS: Characteristics, clinical parameters and symptoms were recorded in a retrospective analysis of 108 patients with serologically confirmed hantavirus infection treated in our department. This cohort corresponds in regard to age, time of infection and gender ratio to the characteristics of the overall cases reported in Germany. RESULTS: The frequency of characteristic symptoms of hantavirus disease did not differ between males and females. The median of nadir and peak levels of clinical parameters did not exhibit relevant differences that would point to a more severe course in males or females. The clinical course and duration of hospitalization were similar for both sexes. No relevant differences in renal and pulmonary findings were observed. Males with hantavirus disease exhibited more cardiac findings than females.To compare the unequal gender distribution of the rodent-borne Puumala hantavirus disease with the gender ratio of other infectious diseases, we analyzed the gender ratio for notifiable infections according to their mode of transmission. Our data revealed a general overrepresentation of men in infections carried by arthropods and rodents. CONCLUSIONS: In contrast to reports from other countries, no crucial differences in the symptoms, course or severity of hantavirus disease between infected men and female were observed in our cohort. However behavioural differences may account for the fact that men are more often affected by certain infectious diseases than females.

Lineage specification of parietal epithelial cells requires ß-catenin/Wnt signaling.

ß-Catenin/Wnt signaling is essential during early inductive stages of kidney development, but its role during postinductive stages of nephron development and maturation is not well understood. In this study, we used Pax8Cre mice to target ß-catenin deficiency to renal epithelial cells at the late S-shaped body stage and the developing collecting ducts. The conditional ß-catenin knockout mice formed abnormal kidneys and had reduced renal function. The kidneys were hypoplastic with a thin cortex; a superficial layer of tubules was missing. A high proportion of glomeruli had small, underdeveloped capillary tufts. In these glomeruli, well differentiated podocytes replaced parietal epithelial cells in Bowman's capsule; capillaries toward the outer aspect of these podocytes mimicked the formation of glomerular capillaries. Tracing nephrogenesis in embryonic conditional ß-catenin knockout mice revealed that these "parietal podocytes" derived from precursor cells in the parietal layer of the S-shaped body by direct lineage switch. Taken together, these findings demonstrate that ß-catenin/Wnt signaling is important during the late stages of nephrogenesis and for the lineage specification of parietal epithelial cells.

Pathogenic old world hantaviruses infect renal glomerular and tubular cells and induce disassembling of cell-to-cell contacts.

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.